論文 - 山本　和子

Low humoral immune response to the BNT162b2 vaccine against COVID-19 in nursing home residents undergoing hemodialysis: a case–control observational study

Mineaki Kitamura, Takahiro Takazono, Kazuko Yamamoto, Takashi Harada, Satoshi Funakoshi, Hiroshi Mukae, Tomoya Nishino

Renal Replacement Therapy ( Springer Science and Business Media LLC )  8 ( 1 ) 8 - 8   2022年12月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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Abstract Background Patients on hemodialysis (HD) face a high mortality risk from coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and they are therefore prioritized for vaccination. However, the efficacy of vaccination in this vulnerable population has not been confirmed. Although age is negatively correlated with serum immunoglobulin (Ig) levels, humoral responses to vaccination in elderly patients undergoing HD have not been investigated. To address this issue, we evaluated the anti-SARS-CoV-2 spike protein antibodies in nursing home residents on HD after BNT162b2 vaccine administration. Methods Patients on HD from a nursing home and care workers (controls) receiving two doses of the BNT162b2 vaccine between April and May 2021 were enrolled in this study. Those with a prior history of COVID-19 were excluded. Anti-spike protein antibodies were measured with the Elecsys (Roche) immunoassay system. Results The study included 26 nursing home residents (41% male; median age, 86 years) and 184 care workers (28% male; median age, 45 years). The median HD vintage was 51 months. After two doses of BNT162b2, 73% of the nursing home residents and 99.5% of the control group developed sufficient anti-spike protein antibodies (> 29 U/mL) to neutralize SARS-CoV-2. Three weeks after the second dose, median IgG titers of the residents and care workers were 83 [interquartile range (IQR) 17–511] and 1365 (IQR 847–2245) U/mL, respectively (p < 0.001). Conclusions The humoral response to BNT162b2 among elderly HD patients was relatively low; therefore, the optimal vaccination strategy for this population should be studied further to avoid COVID-19 outbreaks in healthcare facilities.

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Evaluation of a Triage Checklist for Mild COVID-19 Outpatients in Predicting Subsequent Emergency Department Visits and Hospitalization during the Isolation Period: A Single-Center Retrospective Study

Yasuhiro Tanaka, Kazuko Yamamoto, Shimpei Morimoto, Takeshi Nabeshima, Kayoko Matsushima, Hiroshi Ishimoto, Nobuyuki Ashizawa, Tatsuro Hirayama, Kazuaki Takeda, Hiroshi Gyotoku, Naoki Iwanaga, Shinnosuke Takemoto, Susumu Fukahori, Takahiro Takazono, Hiroyuki Yamaguchi, Takashi Kido, Noriho Sakamoto, Naoki Hosogaya, Shogo Akabame, Takashi Sugimoto, Hirotomo Yamanashi, Kosuke Matsui, Mai Izumida, Ayumi Fujita, Masato Tashiro, Takeshi Tanaka, Koya Ariyoshi, Akitsugu Furumoto, Kouichi Morita, Koichi Izumikawa, Katsunori Yanagihara, Hiroshi Mukae

Journal of Clinical Medicine ( MDPI AG )  11 ( 18 ) 5444 - 5444   2022年09月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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Managing mild illness in COVID-19 and predicting progression to severe disease are concerning issues. Here, we investigated the outcomes of Japanese patients with mild COVID-19, and identified triage risk factors for further hospitalization and emergency department (ED) visits at a single tertiary hospital. A triage checklist with 30 factors was used. Patients recommended for isolation were followed up for 10 days for subsequent ED visits or hospital admission. Overall, 338 patients (median age, 44.0; 45% women) visited the clinic 5.0 days (median) after symptom onset. Thirty-six patients were immediately hospitalized following triage; others were isolated. In total, 72 non-hospitalized patients visited the ED during their isolation, and 30 were hospitalized after evaluation for oxygen desaturation. The median ED visit and hospitalization durations after symptom onset were 5.0 and 8.0 days, respectively. The checklist factors associated with hospitalization during isolation were age > 50 years, body mass index > 25 kg/m2, hypertension, tachycardia with pulse rate > 100/min or blood pressure > 135 mmHg at triage, and >3-day delay in hospital visit after symptom onset. No patients died. Altogether, 80% of patients with mild COVID-19 could be safely isolated at home. Age, BMI, underlying hypertension, date after symptom onset, tachycardia, and systolic blood pressure at triage might be related to later hospitalization.

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Efficacy of <i>Lactococcus lactis</i> strain plasma (LC-Plasma) in easing symptoms in patients with mild COVID-19: protocol for an exploratory, multicentre, double-blinded, randomised controlled trial (PLATEAU study)

Kazuko Yamamoto, Naoki Hosogaya, Tsuyoshi Inoue, Kenta Jounai, Ryohei Tsuji, Daisuke Fujiwara, Katsunori Yanagihara, Koichi Izumikawa, Hiroshi Mukae

BMJ Open ( BMJ )  12 ( 9 ) e061172 - e061172   2022年09月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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Introduction The COVID-19 pandemic has been a major concern worldwide; however, easily accessible treatment options for patients with mild COVID-19 remain limited. Since the oral intake of Lactococcus lactis strain plasma (LC-Plasma) enhances both the innate and acquired immune systems through the activation of plasmacytoid dendritic cells (pDCs), we hypothesised that the oral intake of LC-Plasma could aid the relief or prevention of symptoms in patients with asymptomatic or mild COVID-19. Methods and analysis This is an exploratory, multicentre, double-blinded, randomised, placebo-controlled trial. This study was initiated in December 2021 and concludes in April 2023. The planned number of enrolled subjects is 100 (50 subjects×2 groups); subject enrolment will be conducted until October 2022. Patients with asymptomatic or mild COVID-19 will be enrolled and randomly assigned in a 1:1 ratio to group A (oral intake of LC-Plasma-containing capsule, 200 mg/day, for 14 days) or group B (oral intake of placebo capsule, for 14 days). The primary endpoint is the change in subjective symptoms measured by the severity score. Secondary endpoints include SARS-CoV-2 viral loads, biomarkers for pDC activation, serum SARS-CoV-2-specific antibodies, serum cytokines, interferon and interferon-inducible antiviral effectors and the proportion of subjects with emergency room visits to medical institutions or who are hospitalised. Ethics and dissemination The study protocol was approved by the Clinical Research Review Board of Nagasaki University, in accordance with the Clinical Trials Act of Japan. The study will be conducted in accordance with the Declaration of Helsinki, the Clinical Trials Act, and other current legal regulations in Japan. Written informed consent will be obtained from all the participants. The results of this study will be reported in journal publications. Trial registration number Japan Registry of Clinical Trials (registration number: jRCTs071210097).

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Clinical Differentiation of Severe Fever with Thrombocytopenia Syndrome from Japanese Spotted Fever

Nana Nakada, Kazuko Yamamoto, Moe Tanaka, Hiroki Ashizawa, Masataka Yoshida, Asuka Umemura, Yuichi Fukuda, Shungo Katoh, Makoto Sumiyoshi, Satoshi Mihara, Tsutomu Kobayashi, Yuya Ito, Nobuyuki Ashizawa, Kazuaki Takeda, Shotaro Ide, Naoki Iwanaga, Takahiro Takazono, Masato Tashiro, Takeshi Tanaka, Seiko Nakamichi, Konosuke Morimoto, Koya Ariyoshi, Kouichi Morita, Shintaro Kurihara, Katsunori Yanagihara, Akitsugu Furumoto, Koichi Izumikawa, Hiroshi Mukae

Viruses ( MDPI AG )  14 ( 8 ) 1807 - 1807   2022年08月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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Severe fever with thrombocytopenia syndrome (SFTS) and Japanese spotted fever (JSF; a spotted fever group rickettsiosis) are tick-borne zoonoses that are becoming a significant public health threat in Japan and East Asia. Strategies for treatment and infection control differ between the two; therefore, initial differential diagnosis is important. We aimed to compare the clinical characteristics of SFTS and JSF based on symptomology, physical examination, laboratory data, and radiography findings at admission. This retrospective study included patients with SFTS and JSF treated at five hospitals in Nagasaki Prefecture, western Japan, between 2013 and 2020. Data from 23 patients with SFTS and 38 patients with JSF were examined for differentiating factors and were divided by 7:3 into a training cohort and a validation cohort. Decision tree analysis revealed leukopenia (white blood cell [WBC] &lt; 4000/μL) and altered mental status as the best differentiating factors (AUC 1.000) with 100% sensitivity and 100% specificity. Using only physical examination factors, absence of skin rash and altered mental status resulted in the best differentiating factors with AUC 0.871, 71.4% sensitivity, and 90.0% specificity. When treating patients with suspected tick-borne infection, WBC &lt; 4000/µL, absence of skin rash, and altered mental status are very useful to differentiate SFTS from JSF.

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A Case of Pulmonary Langerhans Cell Histiocytosis That Progressed From a Single-system to a Multisystem Form Despite Smoking Cessation: A Case Report.

Hiroshi Ishimoto, Noriho Sakamoto, Mutsumi Ozasa, Takeharu Katoh, Hidehiro Itonaga, Makoto Wataya, Daisuke Takao, Atsuko Hara, Takashi Kido, Hiroyuki Yamaguchi, Kazuko Yamamoto, Yasushi Obase, Yuji Ishimatsu, Yasushi Miyazaki, Hiroshi Mukae

Internal medicine (Tokyo, Japan)   62 ( 6 ) 877 - 880   2022年08月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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A 36-year-old Japanese man presented with cavities and nodular shadows in the lower lobes of his lungs and osteolytic lesions in the thoracic spine. He was diagnosed with multisystem Langerhans cell histiocytosis (LCH). Three years earlier, he had been noted to have small cavities and granular lesions noted in the upper lobes of his lungs, which later improved with smoking cessation. It was likely that his single-system pulmonary LCH (PLCH) progressed to multisystem LCH despite smoking cessation. Relapse or progression may occur in cases where PLCH lesions improve after smoking cessation. Thus, close follow-up is vital.

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A comparison of liposomal amphotericin B alone and in combination with flucytosine in the treatment of non-HIV Cryptococcal meningitis: A nationwide observational study.

Takahiro Takazono, Yusuke Hidaka, Shimpei Morimoto, Masato Tashiro, Nobuyuki Ashizawa, Tatsuro Hirayama, Kazuaki Takeda, Naoki Iwanaga, Naoki Hosogaya, Kazuko Yamamoto, Kiyohide Fushimi, Katsunori Yanagihara, Hiroshi Mukae, Koichi Izumikawa

Mycoses   65 ( 9 ) 897 - 902   2022年07月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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BACKGROUND: Cryptococcal meningitis (CM) is an opportunistic infectious disease that occurs in immunocompromised hosts, not only in patients living with HIV, but also in patients without HIV. The evidence regarding the treatment for CM in patients without HIV is mainly found in small retrospective studies and is extremely limited. OBJECTIVES: In the present study, we compared the efficacy of liposomal amphotericin B (L-AMB) alone and in combination with flucytosine (5-FC) for the induction treatment of CM in patients without HIV. PATIENTS/METHODS: Data was gathered from the Japanese Diagnosis Procedure Combination database obtained from hospitals throughout Japan. The study included 517 patients without HIV but having CM who fulfilled the inclusion and exclusion criteria. We analyzed the average effect of adding 5-FC to L-AMB treatment using the survival time within 14 days of the diagnosis after adjustment of the baseline clinical characteristics with associations with both selections of the treatment and the prognosis. RESULTS: A total of 146 and 217 CM patients received L-AMB and L-AMB with 5-FC, respectively, within 7 days of diagnosis. L-AMB with 5-FC showed better prognosis than L-AMB on day 14 (mortality 6% vs. 11%, hazard ratio, 0.5775; 95% confidence interval, 0.2748-1.213; p = 0.1, Wald test). CONCLUSIONS: From the results of this real-world database study, we revealed that the combination therapy of 5-FC on L-AMB for induction therapy might have an advantage on the survival time of NHNT patients with CM as well as PLHIV patients with CM.

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Pulmonary and Intestinal Involvement in a Patient with Myeloperoxidase-specific Antineutrophil Cytoplasmic Antibody-positive Hermansky-Pudlak Syndrome.

Takatomo Tokito, Noriho Sakamoto, Hiroshi Ishimoto, Daisuke Okuno, Takuto Miyamura, Atsuko Hara, Takashi Kido, Kazuko Yamamoto, Hiroyuki Yamaguchi, Yasushi Obase, Yuko Akazawa, Ken Okamura, Tamio Suzuki, Yuji Ishimatsu, Hiroshi Mukae

Internal medicine     2022年06月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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A 26-year-old Japanese woman was admitted with a 1-month history of diarrhea, a high fever for a few days, and exacerbation of dyspnea. She was treated with an antifibrotic drug and long-term oxygen therapy for Hermansky-Pudlak syndrome-related pulmonary fibrosis. New ground-glass attenuation appeared on chest computed tomography (CT), and a colon biopsy showed an inflammatory cell accumulation with a high titer of myeloperoxidase (MPO)-specific anti-neutrophil cytoplasmic antibodies (ANCA). Systemic inflammation related to MPO-ANCA titer elevation was suspected. Steroid pulse therapy and intravenous cyclophosphamide improved chest CT findings and diarrhea. Therefore, immunosuppressant treatment should be considered for systemic inflammation related to MPO-ANCA.

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Parameters affecting prognosis after hemodialysis withdrawal: experience from a single center.

Kosei Yamaguchi, Mineaki Kitamura, Takahiro Takazono, Kazuko Yamamoto, Junichiroh Hashiguchi, Takashi Harada, Satoshi Funakoshi, Hiroshi Mukae, Tomoya Nishino

Clinical and experimental nephrology   26 ( 10 ) 1022 - 1029   2022年06月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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INTRODUCTION: Withdrawal from maintenance hemodialysis is unavoidable in some patients due to their poor general condition; however, their survival days vary depending on their health status. The factors associated with life prognosis in the terminal phase in patients undergoing hemodialysis remain unclear. METHODS: Patients who died after withdrawal from hemodialysis between 2011 and 2021 at Nagasaki Renal Center were included. Patient background data were collected, and the association between the patients' clinical features and survival duration was analyzed. RESULTS: The withdrawal group included 174 patients (79.8 ± 10.8 years old; 50.6% male; median dialysis vintage, 3.6 years). The most common reason for withdrawal (95%) was that hemodialysis was more harmful than beneficial because of the patient's poor general condition. The median time from withdrawal to death was 4 days (interquartile range, 3-10 days). Multivariable Cox proportional regression analysis showed that oral nutrition (hazard ratio (HR), 1.98; 95% confidence interval (CI), 1.12-3.50; P = 0.03), hypoxemia (HR, 2.32; 95% CI, 1.55-3.47; P < 0.01), ventilator use (HR, 0.26; 95% CI, 0.11-0.58; P < 0.01), and pleural effusion (HR, 1.54; CI, 1.01-2.37; P = 0.04) were associated with increased survival duration. In contrast, antibiotics and vasopressor administration were not associated with the survival duration. CONCLUSION: In this study, we explored the parameters affecting the survival of patients who withdrew from hemodialysis. Physicians could use our results to establish more accurate predictions, which may help the patient and their family to emotionally accept and implement the desired care plan.

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Macrophage activation syndrome after BNT162b2 mRNA vaccination successfully treated with corticosteroids.

Nobuyuki Ashizawa, Takahiro Takazono, Masataka Umeda, Kazuko Yamamoto, Atushi Kawakami, Hiroshi Mukae

Clinical and experimental rheumatology ( Clinical and Experimental Rheumatology )  40 ( 5 ) 1060 - 1060   2022年05月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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Interstitial Pneumonia with HLA-B54 Antigen that Responded Well to Erythromycin: A Case Report.

Hiroshi Ishimoto, Noriho Sakamoto, Atsuko Hara, Takashi Kido, Hiroyuki Yamaguchi, Kazuko Yamamoto, Yasushi Obase, Yuji Ishimatsu, Hiroshi Mukae

Internal medicine (Tokyo, Japan)     2022年04月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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A 65-year-old Japanese man with interstitial pneumonia demonstrated honeycomb lung with thickened walls on chest high-resolution computed tomography (HRCT) and predominance of neutrophils in the cell fraction of the bronchoalveolar lavage fluid. Although there were no centrilobular nodular or branching shadows on chest HRCT suggestive of diffuse panbronchiolitis, he exhibited sinusitis and had the HLA-B54 antigen. With long-term macrolide therapy, the cough and sputum production markedly improved, wall thickening of the honeycomb lung on chest HRCT decreased, and the forced vital capacity increased. Confirming the presence of HLA-B54 antigen may help determine the indication for long-term macrolide therapy in interstitial pneumonia patients.

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Serum Cytokines Usefulness for Understanding the Pathology in Allergic Bronchopulmonary Aspergillosis and Chronic Pulmonary Aspergillosis.

Yuya Ito, Takahiro Takazono, Yasushi Obase, Susumu Fukahori, Nobuyuki Ashizawa, Tatsuro Hirayama, Masato Tashiro, Kazuko Yamamoto, Yoshifumi Imamura, Naoki Hosogaya, Chizu Fukushima, Yoshitomo Morinaga, Katsunori Yanagihara, Koichi Izumikawa, Hiroshi Mukae

Journal of fungi   8 ( 5 )   2022年04月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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Allergic bronchopulmonary aspergillosis (ABPA) and chronic pulmonary aspergillosis (CPA) are important fungal infections caused by Aspergillus species. An overlap of ABPA and CPA has been reported; therefore, it is critical to determine whether the main pathology is ABPA or CPA and whether antifungals are required. In this study, we investigated whether the serum cytokine profile is useful for understanding the pathology and for differentiating between these diseases. We compared the various serum cytokine levels among healthy subjects and patients diagnosed with asthma, ABPA, or CPA at Nagasaki University Hospital between January 2003 and December 2018. In total, 14 healthy subjects, 19 patients with asthma, 11 with ABPA, and 10 with CPA were enrolled. Interleukin (IL) -5 levels were significantly higher in patients with ABPA than in those with CPA, and IL-33 and tumor necrosis factor (TNF) levels were significantly higher in patients with CPA than in those with asthma (p &lt; 0.05, Dunn's multiple comparison test). The sensitivity and specificity of the IL-10/IL-5 ratio (cutoff index 2.47) for diagnosing CPA were 70% and 100%, respectively. The serum cytokine profile is useful in understanding the pathology of ABPA and CPA, and the IL-10/IL-5 ratio may be a novel supplemental biomarker for indicating the pathology of CPA.

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Favorable Humoral Response to Third Dose of BNT162b2 in Patients Undergoing Hemodialysis.

Mineaki Kitamura, Takahiro Takazono, Kosei Yamaguchi, Hideshi Tomura, Kazuko Yamamoto, Takashi Harada, Satoshi Funakoshi, Hiroshi Mukae, Tomoya Nishino

Journal of clinical medicine   11 ( 8 )   2022年04月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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Patients undergoing hemodialysis are known to exhibit low humoral responses to vaccines against severe acute respiratory syndrome coronavirus 2. In this study, we aimed to elucidate the humoral response to the third dose of BNT162b2 (Pfizer) in patients undergoing hemodialysis. We included 279 patients undergoing hemodialysis (69 ± 11 years, 65% male, median dialysis vintage: 69 months) and 189 healthcare workers (45 ± 13 years, 30% male) who received the third dose of BNT162b2. Anti-spike immunoglobulin G (anti-S IgG) antibody levels were measured 3-4.5 months after the second dose and 3 weeks after the third dose and were compared. Despite a significant difference in anti-S IgG antibody levels after the second dose between the two groups (patients: median 215 U/mL and healthcare workers: median 589 U/mL; p &lt; 0.001), no significant difference in anti-S IgG antibody levels after the third dose was observed (patients: median 19,000 U/mL, healthcare workers: median 21,000 U/mL). Except for dialysis vintage (ρ = 0.209, p &lt; 0.001), no other factors correlated with anti-S IgG antibody levels after the third vaccine dose in patients undergoing hemodialysis. Therefore, a favorable response to the third dose of BNT162b2 was observed in patients undergoing hemodialysis, irrespective of their backgrounds.

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Autoimmune pulmonary alveolar proteinosis exacerbated by steroid therapy due to misdiagnosis as anti-aminoacyl-tRNA synthetase (ARS) antibody positive- interstitial pneumonia: a case report.

Hiroshi Ishimoto, Noriho Sakamoto, Hirokazu Yura, Atsuko Hara, Takashi Kido, Hiroyuki Yamaguchi, Kazuko Yamamoto, Yasushi Obase, Yuji Ishimatsu, Minoru Satoh, Hiroshi Mukae

BMC pulmonary medicine   22 ( 1 ) 120 - 120   2022年03月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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BACKGROUND: Anti-aminoacyl-tRNA synthetase (anti-ARS) antibodies are myositis-specific autoantibodies that have been identified in a subset of patients with interstitial pneumonia who do not present with dermatomyositis or polymyositis. Anti-ARS antibody-positive interstitial pneumonia is commonly treated with steroids or immunosuppressive agents and is usually responsive to these therapies. Here, we present in detail a case in which respiratory failure of a patient diagnosed with anti-ARS antibody-positive interstitial pneumonia was exacerbated by treatment with steroids and immunosuppressive agents. Further examination revealed misdiagnosis of this patient and a subsequent diagnosis of autoimmune pulmonary alveolar proteinosis. CASE PRESENTATION: A 66-year-old man presented to the hospital with dyspnea on exertion, which resulted in the detection of interstitial pneumonia. Serum anti-ARS antibodies were detected; however, there were no other findings suggestive of myositis. Pulmonary alveolar proteinosis (PAP) was suspected based on the marked increase in serum KL-6 and chest computed tomography findings. The bronchoalveolar lavage revealed no milky changes in the lavage fluid. After treatment with steroids and initiation of immunosuppressive agents for anti-ARS antibody-positive interstitial pneumonia, respiratory failure and chest imaging findings showed worsening of the condition. Bronchoscopy was repeated, and milk-like alveolar lavage fluid was collected; serum anti-granulocyte macrophage colony-stimulating factor antibody was identified. Steroids and immunosuppressive agents were gradually tapered and discontinued, and the patient's condition stabilized after repeated alveolar lavage under general anesthesia. CONCLUSION: Due to similar presentation, PAP can be misdiagnosed as interstitial pneumonia. If pulmonary lesions due to interstitial pneumonia are exacerbated by immunosuppressive treatment, physicians should reconsider the diagnosis and include PAP in the differential diagnosis.

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Comparison of intra-familial transmission of influenza virus from index patients treated with baloxavir marboxil or oseltamivir using an influenza transmission model and a health insurance claims database.

Shogo Miyazawa, Takahiro Takazono, Naoki Hosogaya, Kazuko Yamamoto, Hideaki Watanabe, Masakazu Fujiwara, Satoki Fujita, Hiroshi Mukae

Clinical infectious diseases ( Oxford University Press (OUP) )    2022年02月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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BACKGROUND: Influenza affects approximately a billion people globally, including >10 million Japanese individuals every year. Baloxavir marboxil (baloxavir [BXM]; a selective cap-dependent endonuclease inhibitor) is approved for influenza treatment in Japan. We compared the incidence of intra-familial transmission of influenza between BXM and oseltamivir (OTV) treatments using a simulation model. METHODS: Using the JMDC claims database, we identified index case (ICs) as the first family member diagnosed with influenza during the 2018-2019 influenza season, and classified the families into BXM or OTV group per the drug dispensed to ICs. Using a novel influenza intra-familial infection model, we simulated the duration of influenza infection in ICs based on agent-specific virus shedding periods. Intra-familial infections were defined as non-IC family members infected during the agent-specific viral shedding period in ICs. The virus incubation periods in the non-IC family members were considered to exclude secondary infections from potentially external exposure. The primary endpoint was proportion of families with intra-familial infections. For between-group comparisons, we used a multivariate logistic regression model. RESULTS: The median proportion of families with intra-familial transmission was 9.57% and 19.35% in the BXM (N=84,672) and OTV (N=62,004) groups, respectively. The multivariate odds ratio of 1.73 (2.5th-97.5th percentiles, 1.68-1.77) indicated a substantially higher incidence of intra-familial infections in the OTV group versus the BXM group. Subgroup analyses by ICs' age category, virus type, and month of onset revealed similar trends favoring BXM. CONCLUSION: BXM treatment of ICs may contribute to a greater reduction in intra-familial influenza transmission than OTV treatment.

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Associations between Chest CT Abnormalities and Clinical Features in Patients with the Severe Fever with Thrombocytopenia Syndrome

Hiroki Ashizawa, Kazuko Yamamoto, Nobuyuki Ashizawa, Kazuaki Takeda, Naoki Iwanaga, Takahiro Takazono, Noriho Sakamoto, Makoto Sumiyoshi, Shotaro Ide, Asuka Umemura, Masataka Yoshida, Yuichi Fukuda, Tsutomu Kobayashi, Masato Tashiro, Takeshi Tanaka, Shungo Katoh, Konosuke Morimoto, Koya Ariyoshi, Shimpei Morimoto, Mya Myat Ngwe Tun, Shingo Inoue, Kouichi Morita, Shintaro Kurihara, Koichi Izumikawa, Katzunori Yanagihara, Hiroshi Mukae

Viruses ( MDPI AG )  14 ( 2 ) 279 - 279   2022年01月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease caused by the SFTS virus. It involves multiple organ systems, including the lungs. However, the significance of the lung involvement in SFTS remains unclear. In the present study, we aimed to investigate the relationship between the clinical findings and abnormalities noted in the chest computed tomography (CT) of patients with SFTS. The medical records of 22 confirmed SFTS patients hospitalized in five hospitals in Nagasaki, Japan, between April 2013 and September 2019, were reviewed retrospectively. Interstitial septal thickening and ground-glass opacity (GGO) were the most common findings in 15 (68.1%) and 12 (54.5%) patients, respectively, and lung GGOs were associated with fatalities. The SFTS patients with a GGO pattern were elderly, had a disturbance of the conscious and tachycardia, and had higher c-reactive protein levels at admission (p = 0.009, 0.006, 0.002, and 0.038, respectively). These results suggested that the GGO pattern in patients with SFTS displayed disseminated inflammation in multiple organs and that cardiac stress was linked to higher mortality. Chest CT evaluations may be useful for hospitalized patients with SFTS to predict their severity and as early triage for the need of intensive care.

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A case of tocilizumab-refractory idiopathic multicentric Castleman's disease successfully treated with sirolimus.

Remi Sumiyoshi, Tomohiro Koga, Kaori Furukawa, Masataka Umeda, Kazuko Yamamoto, Ryoichi Mori, Atsushi Kawakami

Clinical immunology (Orlando, Fla.)   233   108887 - 108887   2021年12月 [ 査読有り ]

掲載種別: 研究論文（その他学術会議資料等）

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mTOR signaling may be a new therapeutic target for IL-6 inhibitor refractory iMCD-NOS.

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Removal of an aspirated tooth from the bronchus using a cryoprobe: A case report.

Hiroshi Ishimoto, Noriho Sakamoto, Sakiko Moriyama, Mayako Murata, Nana Nakada, Atsuko Hara, Takashi Kido, Hiroyuki Yamaguchi, Kazuko Yamamoto, Yasushi Obase, Yuji Ishimatsu, Hiroshi Mukae

Respirology case reports   9 ( 12 ) e0880   2021年12月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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An 88-year-old bedridden man with Alzheimer's disease developed fever and hypoxaemia. Chest radiography showed obstructive pneumonia caused by a foreign body in the airway. Examination using a flexible bronchoscope revealed a silver-crowned molar, thought to have fallen out due to root caries, at the left lower lobe branch. Removal of the foreign body was unsuccessful with grasping or basket forceps, but successful with cryoadhesion using a cryoprobe. Removal of an airway foreign body by a cryoprobe depends on the nature of the foreign body, namely its water content. Therefore, cryoprobes are not inherently suitable for removing foreign bodies of aspirated teeth, but a tooth covered with mucus for a long time after aspiration can be cryoadhered with cryoprobes. Airway foreign bodies that remain in the airway for a long time should also be considered for removal by cryoprobe, regardless of the water content of the material.

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Association between the psoas muscle index and hospitalization for pneumonia in patients undergoing hemodialysis.

Kosei Yamaguchi, Mineaki Kitamura, Takahiro Takazono, Shuntaro Sato, Kazuko Yamamoto, Satoko Notomi, Kenji Sawase, Takashi Harada, Satoshi Funakoshi, Hiroshi Mukae, Tomoya Nishino

BMC nephrology   22 ( 1 ) 394 - 394   2021年11月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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BACKGROUND: Although muscle mass loss and pneumonia are common and crucial issues in hemodialysis (HD) patients, few reports have focused on their association, which remains unclear. This study assessed the association between skeletal muscle mass and the incidence of pneumonia in HD patients using the psoas muscle index (PMI). METHODS: This retrospective study included 330 patients on HD who were treated at a single center between July 2011 and June 2012. The observation period was between July 2011 and June 2021. Demographic, clinical, and HD data were collected, and the associations between PMI and hospitalization due to bacterial pneumonia were evaluated using Cox proportional hazards models adjusted for patients' background data. Additionally, the correlation between patient characteristics and PMI was evaluated using multivariable linear regression. RESULTS: Among 330 patients (mean age, 67.3 ± 13.3; 56.7% male; median dialysis vintage 58 months, (interquartile range [IQR] 23-124), 79 were hospitalized for pneumonia during the observation period (median observation period was 4.5 years [IQR 2.0-9.1]). The multivariable Cox proportional analysis, which was adjusted for age, sex, dialysis vintage, diabetes mellitus, and stroke history and considered death as a competing risk, indicated that decreased PMI/(standard deviation) was closely associated with the development of pneumonia (hazard ratio: 0.67, 95% confidence interval: 0.47-0.95, p = 0.03). CONCLUSIONS: Skeletal muscle mass was associated with the development of pneumonia in patients on HD and could be a useful marker for the risk of pneumonia.

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Mycobacterium abscessusによる肺抗酸菌症の予後因子の検討

巌水 慧, 山本 和子, 井手口 周平, 井手 昇太郎, 高園 貴弘, 高橋 健介, 赤松 紀彦, 泉川 公一, 柳原 克紀, 迎 寛

日本呼吸器学会誌 ( (一社)日本呼吸器学会 )  10 ( 6 ) 449 - 456   2021年11月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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肺Mycobacterium abscessus症(肺Mab症)患者を単施設で13年間後方視的に調査し、予後因子を検討した。肺Mab症10例中の死亡例3例は、背景肺疾患と免疫抑制薬使用歴を有し、亜種はM.abscessus subsp.abscessusであった。低いperformance status、低アルブミン血症、低いFEV1/VC、治療後の末梢血リンパ球数回復不良が、肺Mab症患者の死亡と関連していた。また、栄養・免疫状態や肺機能の悪い宿主に肺Mab症が合併すると予後不良となることが示唆された。(著者抄録)

HLA-B54 is an independent risk factor for pneumonia in Japanese patients with interstitial lung disease: A multicenter retrospective cohort study.

Noriho Sakamoto, Hiroshi Ishimoto, Masahiro Tahara, Takashi Kido, Atsuko Hara, Takuto Miyamura, Daisuke Okuno, Takatomo Tokito, Sumako Yoshioka, Shimpei Morimoto, Takahiro Takazono, Kazuko Yamamoto, Hiroyuki Yamaguchi, Yasushi Obase, Yuji Ishimatsu, Kazuhiro Yatera, Hiroshi Mukae

Respiratory medicine   188   106612 - 106612   2021年11月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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PURPOSE: Pneumonia is a major cause of respiratory-related hospitalization and an important prognostic factor in patients with chronic interstitial lung disease (ILD). However, the relationship between the incidence of pneumonia and human leukocyte antigen (HLA) serotype has not been fully elucidated. Therefore, this study aimed to determine if there is a relationship between HLA serotype and the incidence of pneumonia in Japanese patients with ILD. METHODS: The medical records of patients with ILD treated at any of three centers in Japan were reviewed to determine their HLA-A and HLA-B serotypes. The characteristics of patients with and without pneumonia were compared. Cox regression analysis was performed to identify risk factors for pneumonia and death in these patients. RESULTS: One hundred and forty-four patients with ILD (pneumonia group, n = 27; non-pneumonia group, n = 117) and complete HLA serology data available were included. HLA-B54 positivity was significantly more common in the pneumonia group than in the non-pneumonia group (37.0% vs. 15.4%, p = 0.010). HLA-B54 positivity was also a significant risk factor for pneumonia (hazard ratio [HR] 4.166, 95% confidence interval [CI] 1.862-9.320, p = 0.001) and death (HR 4.050, 95% CI 1.581-10.374, p = 0.004) in patients with ILD. Furthermore, HLA-B54 positivity was a significant risk factor for pneumonia (HR 3.964, 95% CI 1.392-11.090, p = 0.010) and death (HR 8.131, 95% CI 1.763-37.494, p = 0.007) in patients with idiopathic pulmonary fibrosis. CONCLUSION: HLA-B54 positivity was a significant risk factor for pneumonia and death in patients with ILD, including those with idiopathic pulmonary fibrosis.

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Discrepancy of SARS-CoV-2 PCR results due to the sample collection sites and possible improper sampling.

Satoshi Irifune, Nobuyuki Ashizawa, Takahiro Takazono, Pierre Mutantu, Takeshi Nabeshima, Mya Myat Ngwe Tun, Kenji Ota, Tatsuro Hirayama, Ayumi Fujita, Masato Tashiro, Takeshi Tanaka, Kazuko Yamamoto, Yoshifumi Imamura, Taiga Miyazaki, Toyomitsu Sawai, Koichi Izumikawa, Katsunori Yanagihara, Kouichi Morita, Hiroshi Mukae

Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy   27 ( 10 ) 1525 - 1528   2021年10月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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Polymerase chain reaction (PCR) testing for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is necessary for confirming a diagnosis of Coronavirus disease 2019 (COVID-19). Here we present a COVID-19 case of an elderly woman whose SARS-CoV-2 PCR tests showed false negative repeatedly by evaluating with different sampling sites and procedures. Nasopharyngeal swabs, suctioned sputum, and tongue swabs were collected for SARS-CoV-2-PCR. As for tongue swabs, we compared between two different sample conditions; one obtained with dry condition and the other obtained with moistened condition inside the oral cavity. SARS-CoV-2-PCR showed positive for an extended period with suctioned sputum samples compared with nasopharyngeal swabs and tongue swabs. No SARS-CoV-2 from a nasopharyngeal swab sample obtained on day 46 after symptoms onset was isolated despite high viral load (183740.5 copies/5μL). An adequate production of neutralizing antibody in a serum sample on day 46 was also confirmed. The number of RNA copies of the tongue swab samples was higher with moistened condition than with dry condition. The present case suggests that the difference of sampling site or sample condition can affect PCR results. High loads viral RNA detection does not always correlate with infectivity.

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A case of Lemierre's syndrome with double vision as the first symptom.

Koki Fukushima, Takahiro Takazono, Nobuyuki Ashizawa, Shintaro Hara, Kyoko Kitaoka, Reiko Ideguchi, Teiichiro Miyazaki, Tatsuro Hirayama, Kazuko Yamamoto, Yoshifumi Imamura, Taiga Miyazaki, Koichi Izumikawa, Hiroshi Mukae

Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy   28 ( 2 ) 286 - 289   2021年09月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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Lemierre's syndrome is a serious disease that typically causes oropharyngeal infection with internal jugular vein thrombosis, followed by distant infection focus, such as septic pulmonary embolism. The main causative organisms are anaerobic bacteria in the oral cavity, namely Fusobacterium necrophorum. We encountered an extremely rare case of Lemierre's syndrome, where double vision was found to be the first symptom. The patient's blood culture results showed the presence of F. nucleatum, which spread from the sphenoid sinus to the skull base because of chronic sinusitis; the patient presented with longus colli abscess, clivus osteomyelitis, venous thrombosis, and hematogenous infection. Antibiotic treatment with sulbactam/ampicillin was continued for 14 weeks, and no recurrence has been observed so far. Lemierre's syndrome can be complicated with atypical symptoms such as double vision if the cranial nerves are involved. It might be important to consider this disease in the differential diagnosis in the presence of cranial nerve symptoms of unknown origin with fever or inflammatory findings.

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Association between Serum Phosphate Levels and the Development of Aortic Stenosis in Patients Undergoing Hemodialysis

Miki Torigoe, Mineaki Kitamura, Kosei Yamaguchi, Takumi Uchino, Kenta Torigoe, Takashi Harada, Satoshi Funakoshi, Kazuko Yamamoto, Koji Maemura, Kiyoyuki Eishi, Hiroshi Mukae, Tomoya Nishino

Journal of Clinical Medicine ( MDPI AG )  10 ( 19 ) 4385 - 4385   2021年09月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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We aimed to investigate the factors associated with the development of aortic stenosis (AS) in patients undergoing hemodialysis (HD), and to elucidate the prognosis of HD patients with AS. Patients on HD that had also undergone echocardiography at Nagasaki Renal Center between July 2011 and June 2012 were included. Patients with AS at the time of inclusion were excluded. The diagnosis of AS was based on an annual routine or additional echocardiography. The patients were followed up until June 2021. The association between patient background and AS was also evaluated. Of the 302 patients (mean age, 67.4 ± 13.3 years; male, 58%; median dialysis history, 4.7 years), 60 developed AS and 10 underwent aortic valve replacement. A Cox proportional hazards model revealed that age (hazard ratio (HR), 1.07; 95% confidential interval (CI), 1.04–1.10; p &lt; 0.001) and serum phosphate levels (HR, 1.40; 95%CI, 1.16–1.67, p &lt; 0.001) were independent risk factors for developing AS. Incidentally, there was no significant mortality difference between patients with AS and those without (p = 0.53). Serum phosphate levels are a risk factor for developing AS and should be controlled. Annual echocardiography may contribute to the early detection of AS and improves the prognosis of patients undergoing HD.

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Efficacy of clarithromycin in patients with mild COVID-19 pneumonia not receiving oxygen administration: protocol for an exploratory, multicentre, open-label, randomised controlled trial (CAME COVID-19 study).

Kazuko Yamamoto, Naoki Hosogaya, Noriho Sakamoto, Haruo Yoshida, Hiroshi Ishii, Kazuhiro Yatera, Koichi Izumikawa, Katsunori Yanagihara, Hiroshi Mukae

BMJ open   11 ( 9 ) e053325   2021年09月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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INTRODUCTION: The COVID-19 pandemic has emerged worldwide. Although several medications have been approved for treating moderate-to-severe COVID-19, very few treatment strategy has been established for patients with mild COVID-19 who do not require oxygen administration. Clarithromycin is a macrolide antimicrobial agent that has been widely used for bacterial respiratory infectious diseases. Clarithromycin also acts an immunomodulating drug and suppresses cytokine storms in viral respiratory diseases, including influenza. In this study, we aim to evaluate the efficacy of clarithromycin in patients with mild COVID-19. METHODS AND ANALYSIS: This is an exploratory, multicentre, open-label, randomised controlled trial. This study was initiated in May 2021 and will end in July 2022. Patients with mild COVID-19 pneumonia who do not require oxygen administration will be enrolled and randomly assigned in a 1:1:1 ratio to group A (administration of clarithromycin 800 mg/day), group B (administration of clarithromycin 400 mg/day) or group C (standard treatment without clarithromycin). The planned number of enrolled patients is 60 (20 patients × three groups). The primary endpoint is the number of days required to improve the clinical symptoms as measured by the severity score. Secondary endpoints include days for recovery of the body temperature, proportion of patients with oxygen administration, inflammatory cytokines, viral load, serum immunoglobulins, peripheral blood lymphocytes, blood biomarkers and pneumonia infiltrations. ETHICS AND DISSEMINATION: The study protocol was approved by the Clinical Research Review Board of Nagasaki University in accordance with the Clinical Trials Act in Japan. The study will be conducted in accordance with the Declaration of Helsinki, the Clinical Trials Act and other current legal regulations in Japan. Written informed consent will be obtained from all the participants. The results of this study will be reported as journal publications. TRIAL REGISTRATION NUMBER: jRCTs071210011.

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Correction to: Clinical and experimental phenotype of azole-resistant Aspergillus fumigatus with a HapE splice site mutation: a case report.

Yuya Ito, Takahiro Takazono, Satoru Koga, Yuichiro Nakano, Nobuyuki Ashizawa, Tatsuro Hirayama, Masato Tashiro, Tomomi Saijo, Kazuko Yamamoto, Yoshifumi Imamura, Taiga Miyazaki, Katsunori Yanagihara, Koichi Izumikawa, Hiroshi Mukae

BMC infectious diseases   21 ( 1 ) 961 - 961   2021年09月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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Assessment of oral health in elderly patients with dementia by measuring volatile sulfur compounds and its relationship with pneumonia development: A pilot study.

Satoru Koga, Takahiro Takazono, Takumi Serita, Nobuyuki Ashizawa, Tatsuro Hirayama, Masato Tashiro, Naoki Hosogaya, Kazuko Yamamoto, Yoshifumi Imamura, Hiroyuki Yamaguchi, Noriho Sakamoto, Yasushi Obase, Katsunori Yanagihara, Koichi Izumikawa, Hiroshi Mukae

Respiratory investigation   60 ( 1 ) 162 - 166   2021年09月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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BACKGROUND: This study aimed to clarify the involvement of anaerobes in aspiration pneumonia by measuring volatile sulfur compounds (VSCs), which are metabolites of anaerobic bacteria in the mouth. METHODS: This study included 84 older adult patients (mean age, 82.5 ± 7.34 years) who had dementia and were hospitalized for more than 6 months. We measured the VSCs in the patient's mouth with Oral Chroma and obtained the data of pneumonia development in the past 6 months. We also evaluated the association or correlation of VSCs and some factors which might be the risk factors of aspiration pneumonia. RESULTS: The development of pneumonia had no significant association with the VSCs in the patient's mouth. CONCLUSION: The present pilot study suggests that anaerobes might not be the main causative pathogens of aspiration pneumonia in older adult patients.

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Infectious Pneumonia and Lower Airway Microorganisms in Patients with Rheumatoid Arthritis.

Shuhei Ideguchi, Kazuko Yamamoto, Masahiro Tahara, Tomohiro Koga, Shotaro Ide, Tatsuro Hirayama, Takahiro Takazono, Yoshifumi Imamura, Taiga Miyazaki, Noriho Sakamoto, Shimpei Morimoto, Koichi Izumikawa, Katsunori Yanagihara, Kazuto Ashizawa, Takatoshi Aoki, Atsushi Kawakami, Kazuhiro Yatera, Hiroshi Mukae

Journal of clinical medicine   10 ( 16 )   2021年08月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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The relationship between microorganisms present in the lower respiratory tract and the subsequent incidence of pneumonia in patients with rheumatoid arthritis is unclear. A retrospective cohort study was designed to include a total of 121 patients with rheumatoid arthritis who underwent bronchoscopy at three hospitals between January 2008 and December 2017. Data on patient characteristics, microorganisms detected by bronchoscopy, and subsequent incidences of pneumonia were obtained from electronic medical records. Patients were divided into groups based on the microorganisms isolated from the lower respiratory tract. The cumulative incidence of pneumonia was assessed using the Kaplan-Meier method, and decision tree analysis was performed to analyze the relation between the presence of microorganisms and the occurrence of pneumonia. The most frequently isolated microbes were Pseudomonas aeruginosa, Staphylococcus aureus, and Haemophilus influenzae. Patients whose samples tested negative for bacteria or positive for normal oral flora were included in the control group. The rate of the subsequent incidence of pneumonia was higher in the P. aeruginosa group than in the control group (p = 0.026), and decision tree analysis suggested that P. aeruginosa and patient performance status were two important factors for predicting the incidence of pneumonia. In patients with rheumatoid arthritis, the presence of P. aeruginosa in the lower respiratory tract was associated with the subsequent incidence of pneumonia.

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Evaluation of four commercial severe acute respiratory coronavirus 2 antibody tests.

Nobuyuki Ashizawa, Takahiro Takazono, Kaname Ohyama, Yoji Nagasaki, Masaki Okamoto, Tatsuro Hirayama, Kensuke Takahashi, Hirotomo Yamanashi, Masato Tashiro, Naoki Hosogaya, Takeshi Tanaka, Kazuko Yamamoto, Yuichi Fukuda, Yoshifumi Imamura, Toshinori Kawanami, Taiga Miyazaki, Toyomitsu Sawai, Kiyoyasu Fukushima, Kazuhiro Yatera, Katsunori Yanagihara, Koichi Izumikawa, Hiroshi Mukae

Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy   27 ( 7 ) 1033 - 1038   2021年07月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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INTRODUCTION: Numerous severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) serological tests exists commercially; however, their performance using clinical samples is limited. Although insufficient to detect SARS-CoV-2 in the early phase of infection, antibody assays can be of great use for surveillance studies or for some coronavirus disease 2019 (COVID-19) patients presenting late to the hospital. METHODS: This study evaluated the sensitivity and specificity of four commercial SARS-CoV-2 lateral flow antibody tests using 213 serum specimens from 90 PCR-positive confirmed COVID-19 patients. Of 59 negative control sera, 50 were obtained from patients with other respiratory infectious diseases before COVID-19 pandemic began while nine were from patients infected with other respiratory viruses, including two seasonal coronaviruses. RESULTS: The varied sensitivities for the four commercial kits were 70.9%, 65.3%, 45.1%, and 65.7% for BioMedomics, Autobio Diagnostics, Genbody, and KURABO, respectively, between sick days 1 and 155 in COVID-19 patients. The sensitivities of the four tests gradually increased over time after infection before sick day 5 (15.0%, 12.5%, 15.0%, and 20.0%); from sick day 11-15 (95.7%, 87.2%, 53.2%, and 89.4%); and after sick day 20 (100%, 100%, 68.6%, and 96.1%), respectively. For severe illness, the sensitivities were quite high in the late phase after sick day 15. The specificities were over 96% for all four tests. No cross-reaction due to other pathogens, including seasonal coronaviruses, was observed. CONCLUSIONS: Our results demonstrated the large differences in the antibody test performances. This ought to be considered when performing surveillance analysis.

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Clinical and experimental phenotype of azole-resistant Aspergillus fumigatus with a HapE splice site mutation: a case report.

Yuya Ito, Takahiro Takazono, Satoru Koga, Yuichiro Nakano, Nobuyuki Ashizawa, Tatsuro Hirayama, Masato Tashiro, Tomomi Saijo, Kazuko Yamamoto, Yoshifumi Imamura, Taiga Miyazaki, Katsunori Yanagihara, Koichi Izumikawa, Hiroshi Mukae

BMC infectious diseases   21 ( 1 ) 573 - 573   2021年06月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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BACKGROUND: The recent increase in cases of azole-resistant Aspergillus fumigatus (ARAf) infections is a major clinical concern owing to its treatment limitations. Patient-derived ARAf occurs after prolonged azole treatment in patients with aspergillosis and involves various cyp51A point mutations or non-cyp51A mutations. The prognosis of patients with chronic pulmonary aspergillosis (CPA) with patient-derived ARAf infection remains unclear. In this study, we reported the case of a patient with ARAf due to HapE mutation, as well as the virulence of the isolate. CASE PRESENTATION: A 37-year-old male was presented with productive cough and low-grade fever. The patient was diagnosed with CPA based on the chronic course, presence of a fungus ball in the upper left lobe on chest computed tomography (CT), positivity for Aspergillus-precipitating antibody and denial of other diseases. The patient underwent left upper lobe and left S6 segment resection surgery because of repeated haemoptysis during voriconazole (VRC) treatment. The patient was postoperatively treated with VRC for 6 months. Since then, the patient was followed up without antifungal treatment but relapsed 4 years later, and VRC treatment was reinitiated. Although an azole-resistant isolate was isolated after VRC treatment, the patient did not show any disease progression in either respiratory symptoms or radiological findings. The ARAf isolated from this patient showed slow growth, decreased biomass and biofilm formation in vitro, and decreased virulence in the Galleria mellonella infection model compared with its parental strain. These phenotypes could be caused by the HapE splice site mutation. CONCLUSIONS: This is the first to report a case demonstrating the clinical manifestation of a CPA patient infected with ARAf with a HapE splice site mutation, which was consistent with the in vitro and in vivo attenuated virulence of the ARAf isolate. These results imply that not all the ARAf infections in immunocompetent patients require antifungal treatment. Further studies on the virulence of non-cyp51A mutations in ARAf are warranted.

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Erythema induratum of Bazin-A subcutaneous granulomatous vasculitis that caused difficulty in walking.

Satoshi Irifune, Kazuko Yamamoto, Sosuke Ishijima, Yuta Koike, Junya Fukuoka, Hiroshi Mukae

International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases   106   183 - 184   2021年05月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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Transition of triazole-resistant Aspergillus fumigatus isolates in a Japanese tertiary hospital and subsequent genetic analysis.

Takahiro Takazono, Yuya Ito, Masato Tashiro, Yuichiro Nakano, Tatsuro Hirayama, Naoki Hosogaya, Tomomi Saijo, Kazuko Yamamoto, Yoshifumi Imamura, Taiga Miyazaki, Katsunori Yanagihara, Shigeru Kohno, Hiroshi Mukae, Koichi Izumikawa

Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy   27 ( 3 ) 537 - 539   2021年03月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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OBJECTIVE: To evaluate the annual variation in the frequency of patient-acquired azole-resistant Aspergillus fumigatus (ARAf), and correlate it to the amount of oral triazole prescribed, in Nagasaki, Japan. METHODS: A. fumigatus isolates from respiratory specimens collected in the Nagasaki University Hospital (NUH) between 1996 and 2017 were included in the study. The amount of oral triazole prescribed in NUH since 2001 was obtained from the medical ordering system. Mutations in cyp51A, hmg1, and erg6 genes of ARAf were also analysed. RESULTS: From a total of 240 ARAf strains, 12 (5%), 6 (2.5%), 15 (6.25%), and 3 (1.25%) strains were resistant to itraconazole (ITC), voriconazole (VRC), to either ITC or VRC, and both triazoles, respectively. The amount of prescribed VRC increased annually, and was three times as large as that of ITC in 2017. All eleven patients harbouring ITC-resistant strains had a history of prior ITC treatment, while only one of six patients harbouring VRC-resistant strains had a history of prior VRC treatment. cyp51A mutations were recorded in 10 strains; however, tandem repeat mutations of the promoter region of cyp51A were not observed. Several azole-resistant strains had non-cyp51A mutations. CONCLUSIONS: The frequency of patient-acquired ARAf is not increasing in Nagasaki, Japan. Furthermore, the prevalence of VRC-induced ARAf was rare despite the remarkable increase in the amount of prescribed VRC. Mutations in genes other than cyp51A should also be considered when ARAf strains are obtained from patients treated with azole antifungals.

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Effects of surgical masks on droplet dispersion under various oxygen delivery modalities.

Takahiro Takazono, Kazuko Yamamoto, Ryuta Okamoto, Shimpei Morimoto, Koichi Izumikawa, Hiroshi Mukae

Critical care (London, England)   25 ( 1 ) 89 - 89   2021年02月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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Duration of antifungal therapy for septic pulmonary embolism caused by Candida albicans from a central venous catheter: A case report.

Daisuke Okuno, Kazuhiro Oshima, Taiga Miyazaki, Nobuyuki Ashizawa, Tatsuro Hirayama, Takahiro Takazono, Tomomi Saijo, Kazuko Yamamoto, Yoshifumi Imamura, Hiroyuki Yamaguchi, Noriho Sakamoto, Yasushi Obase, Koichi Izumikawa, Katsunori Yanagihara, Hiroshi Mukae

Clinical case reports   9 ( 2 ) 707 - 710   2021年02月 [ 査読有り ]

掲載種別: 研究論文（その他学術会議資料等）

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The treatment duration for candidemia with septic pulmonary embolism should be determined based on the clearance of fungus from the bloodstream and improvement of symptoms. The remaining lung nodules may not necessarily indicate persistent infection.

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ERG3-Encoding Sterol C5,6-DESATURASE in Candida albicans Is Required for Virulence in an Enterically Infected Invasive Candidiasis Mouse Model.

Tatsuro Hirayama, Taiga Miyazaki, Makoto Sumiyoshi, Nobuyuki Ashizawa, Takahiro Takazono, Kazuko Yamamoto, Yoshifumi Imamura, Koichi Izumikawa, Katsunori Yanagihara, Shigeru Kohno, Hiroshi Mukae

Pathogens (Basel, Switzerland)   10 ( 1 )   2020年12月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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Gastrointestinal colonization by Candida species is considered the main source of candidemia. The ERG3 gene in Candida albicans encodes a sterol C5,6-desaturase, which is essential for ergosterol biosynthesis. Although ERG3 inactivation shows reduced virulence in mouse models of disseminated candidiasis, the role of ERG3 in intestinal infections is unknown. Here, we infected mice with the C. albicans strains CAE3DU3 and CAF2-1, containing mutant and wild-type ERG3, respectively, and studied gut infection and colonization by these strains. We found that the CAE3DU3 strain showed reduced colonization, pathogenesis, damage to gut mucosa, and chemokine production in the mouse model of invasive candidiasis. Additionally, mice inoculated with CAE3DU3 showed lower mortality than mice inoculated with CAF2-1 (p < 0.0001). Chemokines were less induced in the gut inoculated with CAE3DU3 than in the gut inoculated with CAF2-1. Histopathologically, although the wild-type gene was associated with a higher pathogenicity and invasion of the gut mucosa and liver tissues causing remarkable tissue necrosis, the erg3/erg3 mutant was associated with a higher accumulation of cells and lower damage to surrounding tissues than wild-type ERG3. These results establish that the ergosterol biosynthetic pathway may be associated with C. albicans gut colonization and subsequent dissemination.

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Diagnostic evaluation of serum (1, 3)-β-d-glucan levels using the Fungitec G-Test MK kit for Pneumocystis jirovecii pneumonia (PCP) in non-HIV patients.

Shuhei Ideguchi, Kazuko Yamamoto, Tatsuro Hirayama, Takahiro Takazono, Yoshifumi Imamura, Taiga Miyazaki, Noriho Sakamoto, Koichi Izumikawa, Katsunori Yanagihara, Shimpei Morimoto, Hiroshi Mukae

Medical mycology     2020年12月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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Pneumocystis jirovecii pneumonia (PCP) is an opportunistic and life-threatening pulmonary infection with an increasing prevalence among individuals who are human immunodeficiency virus (HIV)-negative. Evidence regarding diagnostic testing of PCP in this patient population is insufficient. We evaluated the performance of serum (1, 3)-β-d-glucan (BDG) using the Fungitec G-test MK kit for diagnosing PCP in non-HIV patients. We retrospectively analyzed data from 219 non-HIV adult patients who underwent bronchoscopy and were tested for P. jirovecii DNA by PCR using lavage samples from the lower respiratory tract. Fifty PCP patients and 125 non-PCP patients were included. The most common underlying diseases were malignancies and systemic autoimmune diseases. Using the serum BDG Fungitec G-test MK test to diagnose PCP, the area under the receiver operating characteristic curve (AUC) was 0.924, whereas the modified cut-off value of 36.6 pg/mL had a sensitivity and specificity of 92.0% and 84.8%, respectively. The AUC for patients with systemic autoimmune diseases was 0.873, and the accuracy of serum BDG test declined when using methotrexate (MTX). In conclusion, the serum BDG test was useful for diagnosing PCP in non-HIV patients; however, the results should be carefully interpreted in case of MTX administration. LAY SUMMARY: The Fungitec G-test MK kit for measuring serum (1, 3)-β-d-glucan (BDG) levels had a sufficient diagnostic performance for Pneumocystis jirovecii pneumonia (PCP) in human immunodeficiency virus-negative patients. However, the results should be carefully interpreted in case of MTX administration.

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Influenza A (H3N2) infection followed by anti-signal recognition particle antibody-positive necrotizing myopathy: A case report.

Jun Iriki, Kazuko Yamamoto, Hiroaki Senju, Atsushi Nagaoka, Masataka Yoshida, Keisuke Iwasaki, Nobuyuki Ashizawa, Tatsuro Hirayama, Masato Tashiro, Takahiro Takazono, Yoshifumi Imamura, Taiga Miyazaki, Koichi Izumikawa, Katsunori Yanagihara, Akira Tsujino, Junya Fukuoka, Masataka Uetani, Minoru Satoh, Hiroshi Mukae

International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases   103   33 - 36   2020年11月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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A 60-year-old Japanese woman presented with subacute progressive muscle pain and weakness in her proximal extremities. She was diagnosed with influenza A (H3N2) infection a week before the onset of muscle pain. At the time of admission, she exhibited weakness in the proximal muscles of the upper and lower limbs, elevated serum liver enzymes and creatinine kinase, and myoglobinuria. She did not manifest renal failure and cardiac abnormalities, indicating myocarditis. Electromyography revealed myogenic changes, and magnetic resonance imaging of the upper limb showed abnormal signal intensities in the muscles, suggestive of myopathy. Muscle biopsy of the biceps revealed numerous necrotic regeneration fibers and mild inflammatory cell infiltration, suggesting immune-mediated necrotizing myopathy (IMNM). Necrotized muscle cells were positive for human influenza A (H3N2). Autoantibody analysis showed the presence of antibodies against the signal recognition particle (SRP), and the patient was diagnosed with anti-SRP-associated IMNM. She was resistant to intravenous methylprednisolone pulse therapy but recovered after administration of oral systemic corticosteroids and immunoglobulins. We speculate that the influenza A (H3N2) infection might have triggered her IMNM. Thus, IMNM should be considered as a differential diagnosis in patients with proximal muscle weakness that persists after viral infections.

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Clinical significance of a positive Clostridioides difficile glutamate dehydrogenase test on the outcomes of hospitalized older patients.

Yohsuke Nagayoshi, Kazuko Yamamoto, Shuntaro Sato, Naofumi Suyama, Takuya Izumikawa, Kinichi Izumikawa, Taiga Miyazaki, Koichi Izumikawa, Katsunori Yanagihara, Hiroshi Mukae

Geriatrics & gerontology international   20 ( 12 ) 1138 - 1144   2020年10月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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AIM: Clostridioides difficile infection worsens the outcome of older hospitalized patients; thus, its diagnosis is necessary for the nosocomial infection control. The standard diagnostic test's limited sensitivity for Clostridioides difficile infection, an enzyme immunoassay for Clostridioides difficile toxins, is of clinical concern. Glutamate dehydrogenase detection is usually tested combined with Clostridioides difficile toxins. However, the clinical significance of a positive glutamate dehydrogenase result is unclear. We evaluated the association between positive glutamate dehydrogenase results, in-hospital mortality and hospital stay length among older patients with suspected Clostridioides difficile infection. METHODS: In this retrospective cohort study, we examined the data of patients who received antibiotics (except for Clostridioides difficile infection treatment) after admission and tested for Clostridioides difficile infection using an enzyme immunoassay for Clostridioides difficile toxins and glutamate dehydrogenase in a secondary care hospital located in a rural region with high aging rate, between 2015 and 2018. RESULTS: In total, 188 patients were included (83.5% of them aged >75 years). Glutamate dehydrogenase positivity was independently associated with in-hospital mortality (adjusted odds ratio 2.19, 95% confidence interval 1.14-4.21) and hospital stay length (regression coefficient 16.0, 95% confidence interval 5.15-26.9). Clostridioides difficile toxin positivity was independently associated with hospital stay duration (regression coefficient 14.5, 95% confidence interval 0.04-29.1), unlike in-hospital mortality. CONCLUSIONS: Glutamate dehydrogenase was closely related to in-hospital mortality and prolonged hospitalization compared with Clostridioides difficile toxin. Clinicians should not neglect glutamate dehydrogenase-positive patients, even when they are Clostridioides difficile toxin-negative, and consider them as having poor prognostic potential. Geriatr Gerontol Int 2020; ••: ••-••.

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Novel and potent antimicrobial effects of caspofungin on drug-resistant Candida and bacteria.

Makoto Sumiyoshi, Taiga Miyazaki, Juliann Nzembi Makau, Satoshi Mizuta, Yoshimasa Tanaka, Takeshi Ishikawa, Koichi Makimura, Tatsuro Hirayama, Takahiro Takazono, Tomomi Saijo, Hiroyuki Yamaguchi, Shintaro Shimamura, Kazuko Yamamoto, Yoshifumi Imamura, Noriho Sakamoto, Yasushi Obase, Koichi Izumikawa, Katsunori Yanagihara, Shigeru Kohno, Hiroshi Mukae

Scientific reports   10 ( 1 ) 17745 - 17745   2020年10月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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Echinocandins, including caspofungin, micafungin, and anidulafungin, are first-line antifungal agents for the treatment of invasive candidiasis. They exhibit fungicidal activity by inhibiting the synthesis of β-1,3-D-glucan, an essential component of the fungal cell wall. However, they are active only against proliferating fungal cells and unable to completely eradicate fungal cells even after a 24 h drug exposure in standard time-kill assays. Surprisingly, we found that caspofungin, when dissolved in low ionic solutions, had rapid and potent antimicrobial activities against multidrug-resistant (MDR) Candida and bacteria cells even in non-growth conditions. This effect was not observed in 0.9% NaCl or other ion-containing solutions and was not exerted by other echinocandins. Furthermore, caspofungin dissolved in low ionic solutions drastically reduced mature biofilm cells of MDR Candida auris in only 5 min, as well as Candida-bacterial polymicrobial biofilms in a catheter-lock therapy model. Caspofungin displayed ion concentration-dependent conformational changes and intracellular accumulation with increased reactive oxygen species production, indicating a novel mechanism of action in low ionic conditions. Importantly, caspofungin dissolved in 5% glucose water did not exhibit increased toxicity to human cells. This study facilitates the development of new therapeutic strategies in the management of catheter-related biofilm infections.

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An adult case of invasive pneumococcal disease due to serotype 12F-specific polysaccharide antibody failure following a 23-valent polysaccharide vaccination.

Yasuhiro Tanaka, Kazuko Yamamoto, Yuichi Fukuda, Asuka Umemura, Masataka Yoshida, Shuhei Ideguchi, Nobuyuki Ashizawa, Tatsuro Hirayama, Masato Tashiro, Takahiro Takazono, Yoshifumi Imamura, Taiga Miyazaki, Koichi Izumikawa, Katsunori Yanagihara, Bin Chang, Hiroshi Mukae

Emerging microbes & infections   9 ( 1 ) 2266 - 2268   2020年10月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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A 68-year-old Japanese man was admitted to our hospital for an acute febrile illness with shivering and impaired consciousness. He was a previous smoker and had a history of chronic obstructive pulmonary disease, for which he inhaled steroid with a long-acting bronchodilator. He had received a 23-valent pneumococcal polysaccharide vaccination 2 years previously. He was intubated and placed on a ventilator in intensive care unit because of acute respiratory failure and hypercapnia. Streptococcus pneumoniae was grown from his blood, sputum, and urine cultures, and he was diagnosed with invasive pneumococcal disease with acute renal failure. He was treated with intravenous beta-lactam and macrolide with continuous hemodiafiltration and was discharged 3 months later. The pneumococcus was identified as serotype 12F, and his serotype-specific IgG and opsonophagocytic index against serotype 12F indicating a lack of protection from IPD among PPV23 serotypes. This case highlights that some individuals may have a serotype-specific polysaccharide antibody failure that makes them susceptible to serotype 12F invasive pneumococcal disease. This case also illustrates the need for serotype-specific IgG and opsonophagocytic index titre cut-offs for each specific pneumococcal serotype in available vaccines to understand the vaccination protection for individual patients better.

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Human immunodeficiency virus-associated vacuolar encephalomyelopathy with granulomatous-lymphocytic interstitial lung disease improved after antiretroviral therapy: a case report.

Kazumasa Akagi, Kazuko Yamamoto, Asuka Umemura, Shotaro Ide, Tatsuro Hirayama, Takahiro Takazono, Yoshifumi Imamura, Taiga Miyazaki, Noriho Sakamoto, Hirokazu Shiraishi, Hideaki Takahata, Yoshiaki Zaizen, Junya Fukuoka, Minoru Morikawa, Kazuto Ashizawa, Katsuji Teruya, Koichi Izumikawa, Hiroshi Mukae

AIDS research and therapy   17 ( 1 ) 38 - 38   2020年07月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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BACKGROUND: Vacuolar encephalomyelopathy, a disregarded diagnosis lately, was a major neurological disease in the terminal stages of human immunodeficiency virus (HIV)-1 infection in the pre-antiretroviral therapy (ART) era. Granulomatous-lymphocytic interstitial lung disease (GLILD) was classically identified as a non-infectious complication of common variable immunodeficiency; however, it is now being recognized in other immunodeficiency disorders. Here, we report the first case of GLILD accompanied by vacuolar encephalomyelopathy in a newly diagnosed HIV-infected man. CASE PRESENTATION: A 40-year-old Japanese man presented with chronic dry cough and progressing paraplegia. Radiological examination revealed diffuse pulmonary abnormalities in bilateral lungs, focal demyelinating lesions of the spinal cord, and white matter lesions in the brain. He was diagnosed with GLILD based on marked lymphocytosis detecting in bronchoalveolar lavage, and transbronchial-biopsy proven T-cellular interstitial lung disease with granulomas. Microbiological examinations did not reveal an etiologic agent. The patient was also diagnosed with HIV-associated vacuolar encephalomyelopathy on the basis of an elevated HIV viral load in cerebrospinal fluid. After initiating ART, the brain lesions and paraplegia improved significantly, and interstitial abnormalities of the lungs and cough disappeared. CONCLUSION: This report highlights that even in the post-ART era in developed countries with advanced healthcare services, HIV-associated vacuolar encephalomyelopathy should be considered in the differential diagnosis of a progressive neurological disorder during the first visit. Furthermore, GLILD may represent an HIV-associated pulmonary manifestation that can be treated by ART.

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Discrepancies in preferences regarding the care of terminal-phase pneumonia in elderly patients among patients, families, and doctors: A multicenter questionnaire survey in nagasaki, Japan.

Takahiro Takazono, Yoshifumi Imamura, Kaoru Kawakami, Naoya Yamasaki, Hiroyoshi Shimizu, Katsuhiro Usuki, Maiko Kiyohara, Tatsuro Hirayama, Masato Tashiro, Naoki Hosogaya, Tomomi Saijo, Kazuko Yamamoto, Taiga Miyazaki, Katsunori Yanagihara, Koichi Izumikawa, Hiroshi Mukae

Respiratory investigation   58 ( 6 ) 488 - 494   2020年07月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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BACKGROUND: Before advance care planning, it is essential to understand the differences in preferences for medical care of terminal-phase pneumonia in elderly patients among the patients, their families, and their doctors. This study aimed to clarify these differences and investigate the actual care provided to elderly patients with pneumonia in nursing hospitals. METHODS: Multicenter questionnaire surveys of 179 patients admitted to nursing homes and long-term care beds in hospitals of three healthcare corporations, their families, and their physicians were conducted between January and August 2018. The questionnaires mainly assessed preferences for life-prolonging medical care procedures, including antibiotic treatments, in terminal-phase pneumonia. A follow-up survey regarding the prognosis and the actual care provided by the physicians was conducted 1 year after the first survey. RESULTS: Only 16.2% of the patients had sufficient prior discussions with their families about their care. More families preferred cardiac massage, intubation, and tracheostomy, while fewer families preferred peripheral intravenous fluids or antibiotics than physicians. A total of 30 patients' families (16.7%) answered to withhold antibiotic treatment, while all physicians supported antibiotic administration. The only significant factor related to withholding antibiotics was high age (P = 0.0057). The follow-up survey administered to the doctors revealed that 49 patients (35.7%) had died within one year. Of the 137 patients, 54 patients (39.4%) had developed pneumonia during this observation period and all were treated with antibiotics. CONCLUSIONS: This study revealed large discrepancies between patients/families and physicians regarding preferences for care. Medical staff should make efforts to fill the gap by ensuring advance care planning.

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Roles of Elm1 in antifungal susceptibility and virulence in Candida glabrata.

Yuya Ito, Taiga Miyazaki, Yutaka Tanaka, Takashi Suematsu, Hironobu Nakayama, Akihiro Morita, Tatsuro Hirayama, Masato Tashiro, Takahiro Takazono, Tomomi Saijo, Shintaro Shimamura, Kazuko Yamamoto, Yoshifumi Imamura, Koichi Izumikawa, Katsunori Yanagihara, Shigeru Kohno, Hiroshi Mukae

Scientific reports   10 ( 1 ) 9789 - 9789   2020年06月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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Elm1 is a serine/threonine kinase involved in multiple cellular functions, including cytokinesis, morphogenesis, and drug resistance in Saccharomyces cerevisiae; however, its roles in pathogenic fungi have not been reported. In this study, we created ELM1-deletion, ELM1-reconstituted, ELM1-overexpression, and ELM1-kinase-dead strains in the clinically important fungal pathogen Candida glabrata and investigated the roles of Elm1 in cell morphology, stress response, and virulence. The elm1Δ strain showed elongated morphology and a thicker cell wall, with analyses of cell-wall components revealing that this strain exhibited significantly increased chitin content relative to that in the wild-type and ELM1-overexpression strains. Although the elm1Δ strain exhibited slower growth than the other two strains, as well as increased sensitivity to high temperature and cell-wall-damaging agents, it showed increased virulence in a Galleria mellonella-infection model. Moreover, loss of Elm1 resulted in increased adhesion to agar plates and epithelial cells, which represent important virulence factors in C. glabrata. Furthermore, RNA sequencing revealed that expression levels of 30 adhesion-like genes were elevated in the elm1Δ strain. Importantly, all these functions were mediated by the kinase activity of Elm1. To our knowledge, this is the first report describing the functional characterization of Elm1 in pathogenic fungi.

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A 71-Year-Old Man With Dyspnea and Cough During Chemotherapy

Kazuko Yamamoto, Koji Ando, Moe Tanaka, Hirokazu Yura, Noriho Sakamoto, Yoshiaki Zaizen, Kazuto Ashizawa, Junya Fukuoka, Yasushi Miyazaki, Hiroshi Mukae

Chest ( Elsevier BV )  157 ( 5 ) e165 - e171   2020年05月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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Evaluation of endobronchial volatile sulfur compounds for rapid diagnosis of lung abscesses caused by obligate anaerobes using Oral Chroma™: A pilot study.

Takahiro Takazono, Yoshifumi Imamura, Masayasu Kitamura, Reiko Furugen, Tatsuro Hirayama, Masato Tashiro, Tomomi Saijo, Kazuko Yamamoto, Taiga Miyazaki, Toshiyuki Saito, Koichi Izumikawa, Katsunori Yanagihara, Hiroshi Mukae

Respiratory investigation   58 ( 3 ) 212 - 215   2020年05月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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Endobronchial volatile sulfur compounds in patients with lung abscess or lung cancer were measured using the Oral Chroma™ gas chromatograph. High levels of hydrogen sulfide and methyl mercaptan were observed in some patients with lung abscess but not in patients with lung cancer. Measuring endobronchial volatile sulfur compounds could be useful for the rapid diagnosis of lung abscess caused by obligate anaerobes.

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Detection of viral RNA in diverse body fluids in an SFTS patient with encephalopathy, gastrointestinal bleeding and pneumonia: a case report and literature review.

Kazumasa Akagi, Taiga Miyazaki, Kazuhiro Oshima, Asuka Umemura, Satoshi Shimada, Kouichi Morita, Hiroaki Senju, Masato Tashiro, Takahiro Takazono, Tomomi Saijo, Shintaro Kurihara, Motohiro Sekino, Kazuko Yamamoto, Yoshifumi Imamura, Koichi Izumikawa, Katsunori Yanagihara, Akihiko Uda, Shigeru Morikawa, Tomoki Yoshikawa, Takeshi Kurosu, Masayuki Shimojima, Masayuki Saijo, Hiroshi Mukae

BMC infectious diseases   20 ( 1 ) 281 - 281   2020年04月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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BACKGROUND: Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease that commonly has a lethal course caused by the tick-borne Huaiyangshan banyang virus [former SFTS virus (SFTSV)]. The viral load in various body fluids in SFTS patients and the best infection control measure for SFTS patients have not been fully established. CASE PRESENTATION: A 79-year-old man was bitten by a tick while working in the bamboo grove in Nagasaki Prefecture in the southwest part of Japan. Due to the occurrence of impaired consciousness, he was referred to Nagasaki University Hospital for treatment. The serum sample tested positive for SFTSV-RNA in the genome amplification assay, and he was diagnosed with SFTS. Furthermore, SFTSV-RNA was detected from the tick that had bitten the patient. He was treated with multimodal therapy, including platelet transfusion, antimicrobials, antifungals, steroids, and continuous hemodiafiltration. His respiration was assisted with mechanical ventilation. On day 5, taking the day on which he was hospitalized as day 0, serum SFTSV-RNA levels reached a peak and then decreased. However, the cerebrospinal fluid collected on day 13 was positive for SFTSV-RNA. In addition, although serum SFTSV-RNA levels decreased below the detectable level on day 16, he was diagnosed with pneumonia with computed tomography. SFTSV-RNA was detected in the bronchoalveolar lavage fluid on day 21. By day 31, he recovered consciousness completely. The pneumonia improved by day 51, but SFTSV-RNA in the sputum remained positive for approximately 4 months after disease onset. Strict countermeasures against droplet/contact infection were continuously conducted. CONCLUSIONS: Even when SFTSV genome levels become undetectable in the serum of SFTS patients in the convalescent phase, the virus genome remains in body fluids and tissues. It may be possible that body fluids such as respiratory excretions become a source of infection to others; thus, careful infection control management is needed.

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Virulence assessment of six major pathogenic Candida species in the mouse model of invasive candidiasis caused by fungal translocation.

Tatsuro Hirayama, Taiga Miyazaki, Yuya Ito, Megumi Wakayama, Kazutoshi Shibuya, Kohei Yamashita, Takahiro Takazono, Tomomi Saijo, Shintaro Shimamura, Kazuko Yamamoto, Yoshifumi Imamura, Koichi Izumikawa, Katsunori Yanagihara, Shigeru Kohno, Hiroshi Mukae

Scientific reports   10 ( 1 ) 3814 - 3814   2020年03月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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Gastrointestinal colonization has been considered as the primary source of candidaemia; however, few established mouse models are available that mimic this infection route. We therefore developed a reproducible mouse model of invasive candidiasis initiated by fungal translocation and compared the virulence of six major pathogenic Candida species. The mice were fed a low-protein diet and then inoculated intragastrically with Candida cells. Oral antibiotics and cyclophosphamide were then administered to facilitate colonization and subsequent dissemination of Candida cells. Mice infected with Candida albicans and Candida tropicalis exhibited higher mortality than mice infected with the other four species. Among the less virulent species, stool titres of Candida glabrata and Candida parapsilosis were higher than those of Candida krusei and Candida guilliermondii. The fungal burdens of C. parapsilosis and C. krusei in the livers and kidneys were significantly greater than those of C. guilliermondii. Histopathologically, C. albicans demonstrated the highest pathogenicity to invade into gut mucosa and liver tissues causing marked necrosis. Overall, this model allowed analysis of the virulence traits of Candida strains in individual mice including colonization in the gut, penetration into intestinal mucosa, invasion into blood vessels, and the subsequent dissemination leading to lethal infections.

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Selection of Oral Antifungals for Initial Maintenance Therapy in Chronic Pulmonary Aspergillosis: A Longitudinal Analysis.

Masato Tashiro, Takahiro Takazono, Tomomi Saijo, Kazuko Yamamoto, Yoshifumi Imamura, Taiga Miyazaki, Hiroshi Kakeya, Tsunehiro Ando, Kenji Ogawa, Kazuma Kishi, Issei Tokimatsu, Yuta Hayashi, Satoru Fujiuchi, Katsunori Yanagihara, Yoshitsugu Miyazaki, Kiyoshi Ichihara, Hiroshi Mukae, Shigeru Kohno, Koichi Izumikawa

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America   70 ( 5 ) 835 - 842   2020年02月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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BACKGROUND: There are limited data for direct comparisons of the efficacy of oral itraconazole (ITCZ) and oral voriconazole (VRCZ) therapy in the treatment of chronic pulmonary aspergillosis (CPA). METHODS: We conducted a retrospective, follow-up, observational study of CPA patients enrolled in 2 previous multicenter trials. RESULTS: Of the 273 CPA patients, 59 and 101 patients started maintenance therapy with oral ITCZ and oral VRCZ, respectively, just after the end of acute intravenous therapy in each trial. At the end of the observation period in this follow-up study (median observation period, 731 days), the percentage of patients who showed improvement was lower in the ITCZ group than in the VRCZ group (18.2% vs 40.0%). However, after including stable patients, the percentages were 50.9% and 52.6%, respectively, in the ITCZ and VRCZ groups, which were not significantly different (P = .652). Multivariable Cox regression analysis showed no significant influence of the choice of initial maintenance treatment (ITCZ or VRCZ) on overall mortality as well as CPA-associated mortality. Multivariable logistic regression showed that oral ITCZ selection for initial maintenance therapy was an independent risk factor for hospital readmission and switching to other antifungal agents (odds ratio [OR], 3.1; 95% confidence interval [CI], 1.3-7.5 and OR, 5.7; 95% CI, 2.0-15.7, respectively). CONCLUSIONS: Oral VRCZ for initial maintenance therapy showed better effectiveness than oral ITCZ for clinical improvement in CPA patients. There was no difference in crude mortality between initial maintenance therapy with VRCZ and ITCZ, especially in elderly CPA patients. CLINICAL TRIALS REGISTRATION: UMIN000007055.

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Design and Synthesis of a Class of Compounds That Inhibit the Growth of Fungi Which Cause Invasive Infections

Nana Nakada-Motokawa, Taiga Miyazaki, Satoshi Mizuta, Yoshimasa Tanaka, Tatsuro Hirayama, Takahiro Takazono, Tomomi Saijo, Kazuko Yamamoto, Yoshifumi Imamura, Koichi Izumikawa, Katsunori Yanagihara, Koichi Makimura, Kohsuke Takeda, Shigeru Kohno, Hiroshi Mukae

ChemistrySelect   5 ( 3 ) 1140 - 1145   2020年01月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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© 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Invasive fungal infections are growing causes of morbidity and mortality in immunocompromised patients. However, only one antifungal drug class has been developed in the last 30 years, extremely limiting current therapeutic options. To address unmet medical needs, we performed high-throughput screening of 9600 chemical compounds and identified an aminohydrazone derivative as a novel and potent antifungal compound. We then designed and synthesized a series of aminohydrazone derivatives, and demonstrated that 1-[(E)-[4-(3′,4′-dichlorobenxyloxy)phenyl methylidene]amino]-guanidine had the most potent inhibitory activity and exhibited a broad spectrum of antifungal activities against Candida species (including multidrug resistant C. auris), Aspergillus species, Cryptococcus neoformans, and Rhizopus oryzae. Against C. albicans, the leading cause of Candida infections, the compound had fungicidal activity for planktonic cells at 8 μg mL−1 (25 μM) and anti-biofilm activity at 34 μg mL−1 (100 μM). This study provides new insights for the development of a new drug class for the treatment of invasive fungal infections which are often refractory to conventional therapies.

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Detection of invasive pulmonary aspergillosis in mice using lung perfusion single-photon emission computed tomography with [99mTc]MAA.

Masataka Yoshida, Masato Tashiro, Kodai Nishi, Maki Mishima, Kei Kawano, Takahiro Takazono, Tomomi Saijo, Kazuko Yamamoto, Yoshifumi Imamura, Taiga Miyazaki, Takashi Kudo, Katsunori Yanagihara, Hiroshi Mukae, Koichi Izumikawa

Medical mycology   58 ( 7 ) 965 - 972   2020年01月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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There is an urgent need for development of better diagnostic strategies to improve outcomes in patients with invasive pulmonary aspergillosis (IPA). We hypothesized that lung perfusion single-photon emission computed tomography (SPECT) may be more sensitive and specific than computed tomography (CT) of the chest for detection of IPA because it is an angioinvasive pulmonary infection with characteristics that are different from those of bacterial pneumonia. We used SPECT with injection of technetium-99m-labeled macroaggregated albumin ([99mTc]MAA) to measure pulmonary perfusion in noninfected mice, mice with IPA, and mice with bacterial pneumonia. Histopathologic analysis was performed to evaluate the correlation between the perfusion defect and mould invasion. We also attempted to quantitatively evaluate the SPECT images to identify differences in decreased perfusion levels in affected areas in the mouse lung. Histopathologic analysis in the IPA mouse model showed a clear match between areas with a perfusion defect and the presence of mold, indicating that the location of the perfusion defect on a SPECT image reflects angioinvasion of the mould in the lungs. Some of these perfusion defects could be seen before appearance of the infiltrate of CT images. Quantitative analysis confirmed that perfusion in the affected areas was significantly decreased in the IPA model but not in the bacterial pneumonia model (P < .0001). This imaging method may be preferable to the alternative methods presently used to identify the presence of mold in a patient's lungs.

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Epithelial membrane protein 2 governs transepithelial migration of neutrophils into the airspace

Wan-Chi Lin, Kymberly M. Gowdy, Jennifer H. Madenspacher, Rachel L. Zemans, Kazuko Yamamoto, Miranda Lyons-Cohen, Hideki Nakano, Kyathanahalli Janardhan, Carmen J. Williams, Donald N. Cook, Joseph P. Mizgerd, Michael B. Fessler

Journal of Clinical Investigation ( American Society for Clinical Investigation )  130 ( 1 ) 157 - 170   2020年01月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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Severe Fever with Thrombocytopenia Syndrome Virus RNA in Semen, Japan.

Satoru Koga, Takahiro Takazono, Tsuyoshi Ando, Daisuke Hayasaka, Masato Tashiro, Tomomi Saijo, Shintaro Kurihara, Motohiro Sekino, Kazuko Yamamoto, Yoshifumi Imamura, Taiga Miyazaki, Katsunori Yanagihara, Kouichi Morita, Koichi Izumikawa, Hiroshi Mukae

Emerging infectious diseases   25 ( 11 ) 2127 - 2128   2019年11月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

　概要を見る

Severe fever with thrombocytopenia syndrome virus (SFTSV) can be transmitted between humans. We describe a case of severe fever with thrombocytopenia syndrome in which SFTSV RNA was detected in semen after its disappearance from serum. Our findings indicate possible sexual transmission of this emerging virus.

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The efficacy and safety of sitafloxacin and garenoxacin for the treatment of pneumonia in elderly patients: A randomized, multicenter, open-label trial.

Taiga Miyazaki, Shigeki Nakamura, Kohji Hashiguchi, Tsutomu Kobayashi, Kiyoyasu Fukushima, Yuichi Fukuda, Akira Kondo, Yuichi Inoue, Hironobu Koga, Eisuke Sasaki, Yosuke Nagayoshi, Yasuhito Higashiyama, Masataka Yoshida, Takahiro Takazono, Tomomi Saijo, Yoshitomo Morinaga, Kazuko Yamamoto, Yoshifumi Imamura, Shinya Mikushi, Koichi Izumikawa, Katsunori Yanagihara, Shigeru Kohno, Hiroshi Mukae

Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy   25 ( 11 ) 886 - 893   2019年11月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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Oral treatment for elderly outpatients with pneumonia is becoming increasingly important in this super-aged society from the perspective of cost-effectiveness and limited hospital capacities. We evaluated the efficacy and safety of two oral respiratory quinolones, sitafloxacin and garenoxacin, in elderly patients with pneumonia. This randomized, multicenter, open-label trial was conducted among patients aged ≥65 years with clinically and radiographically confirmed pneumonia in Japan. Patients were randomly assigned (1:1) to receive either sitafloxacin (100 mg/day) or garenoxacin (400 mg/day) for 3-10 days. The primary efficacy endpoint was the clinical cure rate at 5-10 days after the end of treatment. From December 2013 to November 2017, we enrolled 120 patients at 11 hospitals and randomly assigned 59 patients to the sitafloxacin group (1 patient withdrew) and 61 patients to the garenoxacin group. These included 30 patients with nursing and healthcare-associated pneumonia (NHCAP) (18 receiving sitafloxacin, 12 receiving garenoxacin) and 37 patients with aspiration pneumonia (16 receiving sitafloxacin, 21 receiving garenoxacin). The clinical cure rates in the sitafloxacin and garenoxacin groups were 88.5% (95% confidence interval: 76.6-95.6) and 88.9% (95% confidence interval: 77.4-95.8), respectively. No significant differences were observed in the incidence rates of drug-related adverse events between the sitafloxacin (20.7%; 12/58 patients) and garenoxacin (27.9%; 17/61 patients) groups. The most common adverse event was hepatic dysfunction, which occurred in seven patients in each group. We conclude that sitafloxacin and garenoxacin are comparably effective and safe for the treatment of pneumonia, including NHCAP and aspiration pneumonia, in elderly patients.

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Efficacy and safety of cefditoren pivoxil for exacerbations of chronic obstructive pulmonary disease: A prospective multicenter interventional study.

Taiga Miyazaki, Kiyoyasu Fukushima, Kohji Hashiguchi, Yuichi Inoue, Tomo Mihara, Toyomitsu Sawai, Naofumi Suyama, Tsutomu Kobayashi, Akira Kondo, Yuichi Fukuda, Yosuke Harada, Eisuke Sasaki, Norihito Kaku, Shotaro Ide, Takahiro Takazono, Tomomi Saijo, Kosuke Kosai, Yoshitomo Morinaga, Shigeki Nakamura, Kazuko Yamamoto, Yoshifumi Imamura, Koichi Izumikawa, Katsunori Yanagihara, Shigeru Kohno, Hiroshi Mukae

Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy   25 ( 9 ) 702 - 707   2019年09月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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Oral antibiotic therapy for patients with acute exacerbations of chronic obstructive pulmonary disease (COPD) usually involves an aminopenicillin with clavulanic acid, a macrolide, or a quinolone. To date, however, the clinical efficacy and safety of the oral cephalosporin cefditoren pivoxil has not been evaluated in Japanese patients with acute exacerbations of COPD. We conducted a prospective, multicenter, single arm, interventional study from January 2013 to March 2017 to determine the efficacy and safety of oral administration of 200 mg cefditoren pivoxil three times daily for 7 days in a cohort of 29 eligible patients from 15 hospitals. The mean age (SD) of participants was 73.1 (8.1) years and 28 had a smoking history (the mean [SD] of smoking index, 1426.7 [931.7]). The primary efficacy endpoint was clinical response (cure rate) at test of cure, which was set at 5-10 days after treatment ceased. Of the 23 patients finally analyzed, cure was achieved in 15 (65.2%), while 8 (34.8%) remained uncured. Previous experience of acute exacerbations significantly affected the cure rate: none of the three patients who had at least two prior exacerbations were cured, while 15 of the 20 patients with one or fewer prior exacerbations were cured (p = 0.032). The microbiological eradication rate was 88.9% at test of cure. During treatment, mild pneumonia was reported as an adverse event in one patient (3.4%) but resolved within 10 days of onset. We conclude that cefditoren pivoxil represents a viable alternative for antibiotic therapy in patients with few prior exacerbations.

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Munchausen syndrome mimicking refractory subcutaneous abscess with bacteremia, diagnosed by repetitive element sequence-based polymerase chain reaction: a case report.

Iwanaga N, Yamamoto K, Takazono T, Saijo T, Imamura Y, Miyazaki T, Izumikawa K, Yamamoto Y, Yanagihara K, Yasuoka A, Mukae H

Journal of medical case reports   13 ( 1 ) 287 - 287   2019年09月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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BACKGROUND: Rapid diagnosis and appropriate treatment of Munchausen syndrome is important not only for the patient but also for health care workers because a delay in diagnosis can worsen patients' clinical outcomes, and result in a substantial medical cost. CASE PRESENTATION: A young and previously healthy 24-year-old Japanese woman, a nurse, presented with complaints of refractory abscess on her left upper limb for 3 months. A physical examination on admission revealed low-grade fever and a subcutaneous abscess in her left forearm. Laboratory data suggested mild systemic inflammation and liver dysfunction, but no abnormalities of the immune system, including changes in the number of lymphocytes and neutrophils, neutrophil phagocytic capacity, and natural killer (NK) cell activity, were observed. A human immunodeficiency virus test was also negative. Multiple modalities, including positron emission tomography-computed tomography, failed to detect any cause and focus of infection except her left upper limb. Streptococcus mitis and Prevotella buccae were detected from the wound, but no microorganisms were detected in a blood culture. The cellulitis promptly resolved; however, exacerbation of the subcutaneous abscess with polymicrobial bacteremia repeatedly occurred unexpectedly. Because of this puzzling clinical course, the possibility of self-injury was finally suspected. Three syringes with needles, with a turbid liquid, were found in our patient's bag. Enterobacter cloacae and Enterococcus faecalis were detected in the liquid, and an analysis via repetitive element sequence-based polymerase chain reaction determined that Enterococcus faecalis in the wound and syringe contents were genetically identical. She was diagnosed as having Munchausen syndrome and treated with the collaboration of a psychiatrist. She finally confessed that she had injected her own saliva and toilet water into the drip line and wound. CONCLUSIONS: This case report is valuable in that it is the first case in which this syndrome was diagnosed by a genetic method. Munchausen syndrome should not be neglected as a possible cause of refractory and recurrent infection.

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The Novel Arylamidine T-2307 Selectively Disrupts Yeast Mitochondrial Function by Inhibiting Respiratory Chain Complexes.

Kohei Yamashita, Taiga Miyazaki, Yoshiko Fukuda, Junichi Mitsuyama, Tomomi Saijo, Shintaro Shimamura, Kazuko Yamamoto, Yoshifumi Imamura, Koichi Izumikawa, Katsunori Yanagihara, Shigeru Kohno, Hiroshi Mukae

Antimicrobial agents and chemotherapy   63 ( 8 )   2019年08月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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The novel arylamidine T-2307 exhibits broad-spectrum in vitro and in vivo antifungal activities against clinically significant pathogens. Previous studies have shown that T-2307 accumulates in yeast cells via a specific polyamine transporter and disrupts yeast mitochondrial membrane potential. Further, it has little effect on rat liver mitochondrial function. The mechanism by which T-2307 disrupts yeast mitochondrial function is poorly understood, and its elucidation may provide important information for developing novel antifungal agents. This study aimed to determine how T-2307 promotes yeast mitochondrial dysfunction and to investigate the selectivity of this mechanism between fungi and mammals. T-2307 inhibited the respiration of yeast whole cells and isolated yeast mitochondria in a dose-dependent manner. The similarity of the effects of T-2307 and respiratory chain inhibitors on mitochondrial respiration prompted us to investigate the effect of T-2307 on mitochondrial respiratory chain complexes. T-2307 particularly inhibited respiratory chain complexes III and IV not only in Saccharomyces cerevisiae but also in Candida albicans, indicating that T-2307 acts against pathogenic fungi in a manner similar to that of yeast. Conversely, T-2307 showed little effect on bovine respiratory chain complexes. Additionally, we demonstrated that the inhibition of respiratory chain complexes by T-2307 resulted in a decrease in the intracellular ATP levels in yeast cells. These results indicate that inhibition of respiratory chain complexes III and IV is a key factor for selective disruption of yeast mitochondrial function and antifungal activity.

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Evaluation of Candida peritonitis with underlying peritoneal fibrosis and efficacy of micafungin in murine models of intra-abdominal candidiasis.

Nobuyuki Ashizawa, Taiga Miyazaki, Shinichi Abe, Takahiro Takazono, Tomomi Saijo, Yoko Obata, Shintaro Shimamura, Kazuko Yamamoto, Yoshifumi Imamura, Takehiko Koji, Tomoya Nishino, Koichi Izumikawa, Katsunori Yanagihara, Shigeru Kohno, Hiroshi Mukae

Scientific reports   9 ( 1 ) 9331 - 9331   2019年06月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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Candida peritonitis is a crucial disease, however the optimal antifungal therapy regimen has not been clearly defined. Peritoneal fibrosis (PF) can be caused by abdominal surgery, intra-abdominal infection, and malignant diseases, and is also widely recognized as a crucial complication of long-term peritoneal dialysis. However, the influence of PF on Candida peritonitis prognosis remains unknown. Here, we evaluated the severity of Candida peritonitis within the context of PF and the efficacy of micafungin using mice. A PF mouse model was generated by intraperitoneally administering chlorhexidine gluconate. Candida peritonitis, induced by intraperitoneal inoculation of Candida albicans, was treated with a 7-day consecutive subcutaneous administration of micafungin. Candida infection caused a higher mortality rate in the PF mice compared with the control mice on day 7. Proliferative Candida invasion into the peritoneum and intra-abdominal organs was confirmed pathologically only in the PF mice. However, all mice in both groups treated with micafungin survived until day 20. Micafungin treatment tends to suppress inflammatory cytokines in the plasma 12 h after infection in both groups. Our results suggest that PF enhances early mortality in Candida peritonitis. Prompt initiation and sufficient doses of micafungin had good efficacy for Candida peritonitis, irrespective of the underlying PF.

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Evaluation of <i>Aspergillus</i>-Specific Lateral-Flow Device Test Using Serum and Bronchoalveolar Lavage Fluid for Diagnosis of Chronic Pulmonary Aspergillosis.

Takazono T, Ito Y, Tashiro M, Nishimura K, Saijo T, Yamamoto K, Imamura Y, Miyazaki T, Yanagihara K, Mukae H, Izumikawa K

Journal of clinical microbiology   57 ( 5 )   2019年05月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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The Aspergillus-specific lateral-flow device (AspLFD) test is a newly developed point-of-care diagnostic method for invasive pulmonary aspergillosis. However, evidence of the diagnostic performance of the AspLFD for chronic pulmonary aspergillosis (CPA) is limited. Therefore, we conducted a retrospective study to investigate this in comparison with the galactomannan (GM) β-d-glucan (BDG) test. Fifty patients with chronic pulmonary aspergillosis and 65 patients with respiratory disease, as a control, were enrolled in this study. The majority of the CPA disease entities were chronic pulmonary aspergillosis (64.0%, n = 32), followed by subacute invasive pulmonary aspergillosis (IPA) (20.0%, n = 10) and simple pulmonary aspergilloma (SPA) (16.0%, n = 8). The sensitivity and specificity of the AspLFD test in serum samples were 62.0% and 67.7%, respectively. The GM test (cutoff index, 1.54) showed a sensitivity of 22% and a specificity of 92.3%, while the sensitivity and specificity of the BDG test (cutoff, 19.3 pg/ml) were 48% and 90.8%, respectively. In bronchoalveolar lavage fluid samples, the AspLFD test showed a sensitivity of 66.7% and a specificity of 69.2%, while those of the GM test (cutoff index, 0.6) were 72.7% and 83.1%, respectively. The Aspergillus precipitating antibody test had 70% sensitivity. Unlike the Aspergillus precipitating antibody test, the AspLFD on serum samples showed similar sensitivity to non-fumigatus Aspergillus species. Patients with false-positive results for the AspLFD on serum samples were of a significantly higher age and had a higher prevalence of cavitary lesions in chest computed tomography than patients with negative results in the control group. Given the results in this study, the performance of the AspLFD using serum was acceptable as a point-of-care test for the diagnosis of CPA.

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A case of bilateral emphysematous pyelonephritis caused by Candida albicans.

Ideguchi S, Yamamoto K, Ikeda A, Hashimoto K, Takazono T, Saijo T, Imamura Y, Miyazaki T, Mukae H

Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy   25 ( 4 ) 302 - 306   2019年04月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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Emphysematous pyelonephritis (EPN) is a life-threatening renal infection characterized by the formation of gas within the renal parenchyma and collecting duct system, as well as perinephric tissues. We herein report a case of bilateral EPN accompanied by the urinary tract infection caused by spherical growth of Candida albicans in a patient with underlying diabetes mellitus and prostate cancer. The diagnosis was assisted by computed tomography, urography, and gram staining. Despite immediate percutaneous catheter drainage and a 4-week course of antifungal treatment, the C. albicans infection was refractory, as indicated by continuous isolation from the urine, and the patient eventually died. A local autopsy of urinary organs revealed C. albicans in the renal tissue. EPN caused by Candida species frequently occurs in men, and almost all cases have underlying poorly controlled diabetes. This condition is subject to delayed diagnosis, which may lead to extended disease and high mortality. Candida species should be considered as causative microorganism for refractory EPN in patients with poorly controlled diabetes who are receiving antibiotic treatment. Gram staining may contribute to an early diagnosis of EPN caused by Candida species, which may require long-term antifungal therapy.

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Clinical features and cause analysis of false positive results of Aspergillus galactomannan assay in pulmonary cryptococcosis patients.

Takazono T, Saijo T, Ashizawa N, Oshima K, Nishimura K, Tashiro M, Yamamoto K, Imamura Y, Miyazaki T, Yanagihara K, Mukae H, Izumikawa K, Sheppard DC

European journal of clinical microbiology & infectious diseases : official publication of the European Society of Clinical Microbiology   38 ( 4 ) 735 - 741   2019年04月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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There have been conflicting reports of false positive galactomannan assay results in patients with systemic cryptococcosis. We sought to determine the frequency of GM positivity in patients with pulmonary cryptococcosis and confirm the source of this cross-reactivity in vitro. We conducted a retrospective study to elucidate the rate of galactomannan (GM) false positivity and cause in a cohort of 29 patients with pulmonary cryptococcal disease. The production of GM cross-reacting substances by clinical isolates and laboratory isolates of C. neoformans was tested in vitro. The mean serum GM index (Platelia Aspergillus) in patients with pulmonary cryptococcosis was 1.06, with 16 (55.2%) of patients having values above the positive cutoff value of 0.5. GM index values significantly decreased after treatment of cryptococcosis. There was no significant correlation between galactomannan and cryptococcal glucuronoxylomannan antigen (Eiken Latex test) results. Culture supernatants from clinical isolates and wild-type C. neoformans did not react in the GM assay; however, growth in the presence of 6% sodium chloride induced the production of cross-reacting GM antigens in culture supernatants from clinical isolates, wild type and a glucuronoxylomannan-deficient mutant of C. neoformans, but not in culture supernatants from a galactoxylomannan-deficient strain. Our results support the cross-reactivity of cryptococcal galactoxylomannan with the serum GM assay in vitro and in patients with pulmonary cryptococcal infection.

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65歳以上の高齢者肺炎に対するシタフロキサシンとガレノキサシンの有効性と安全性の検討 多施設共同前向きランダム化比較試験

宮崎 泰可, 中村 茂樹, 橋口 浩二, 小林 奨, 福島 喜代康, 福田 雄一, 近藤 晃, 井上 祐一, 古賀 宏延, 佐々木 英祐, 永吉 洋介, 東山 康仁, 高園 貴弘, 西條 知見, 山本 和子, 今村 圭文, 泉川 公一, 柳原 克紀, 河野 茂, 迎 寛

日本化学療法学会雑誌 ( (公社)日本化学療法学会 )  67 ( 2 ) 247 - 248   2019年03月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

Vacuolar proton-translocating ATPase is required for antifungal resistance and virulence of Candida glabrata.

Asuka Minematsu, Taiga Miyazaki, Shintaro Shimamura, Hiroshi Nishikawa, Hironobu Nakayama, Takahiro Takazono, Tomomi Saijo, Kazuko Yamamoto, Yoshifumi Imamura, Katsunori Yanagihara, Shigeru Kohno, Hiroshi Mukae, Koichi Izumikawa

PloS one   14 ( 1 ) e0210883   2019年 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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Vacuolar proton-translocating ATPase (V-ATPase) is located in fungal vacuolar membranes. It is involved in multiple cellular processes, including the maintenance of intracellular ion homeostasis by maintaining acidic pH within the cell. The importance of V-ATPase in virulence has been demonstrated in several pathogenic fungi, including Candida albicans. However, it remains to be determined in the clinically important fungal pathogen Candida glabrata. Increasing multidrug resistance of C. glabrata is becoming a critical issue in the clinical setting. In the current study, we demonstrated that the plecomacrolide V-ATPase inhibitor bafilomycin B1 exerts a synergistic effect with azole antifungal agents, including fluconazole and voriconazole, against a C. glabrata wild-type strain. Furthermore, the deletion of the VPH2 gene encoding an assembly factor of V-ATPase was sufficient to interfere with V-ATPase function in C. glabrata, resulting in impaired pH homeostasis in the vacuole and increased sensitivity to a variety of environmental stresses, such as alkaline conditions (pH 7.4), ion stress (Na+, Ca2+, Mn2+, and Zn2+ stress), exposure to the calcineurin inhibitor FK506 and antifungal agents (azoles and amphotericin B), and iron limitation. In addition, virulence of C. glabrata Δvph2 mutant in a mouse model of disseminated candidiasis was reduced in comparison with that of the wild-type and VPH2-reconstituted strains. These findings support the notion that V-ATPase is a potential attractive target for the development of effective antifungal strategies.

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Autophagy-Inducing Factor Atg1 Is Required for Virulence in the Pathogenic Fungus Candida glabrata.

Shintaro Shimamura, Taiga Miyazaki, Masato Tashiro, Takahiro Takazono, Tomomi Saijo, Kazuko Yamamoto, Yoshifumi Imamura, Koichi Izumikawa, Katsunori Yanagihara, Shigeru Kohno, Hiroshi Mukae

Frontiers in microbiology   10   27 - 27   2019年 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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Candida glabrata is one of the leading causes of candidiasis and serious invasive infections in hosts with weakened immune systems. C. glabrata is a haploid budding yeast that resides in healthy hosts. Little is known about the mechanisms of C. glabrata virulence. Autophagy is a 'self-eating' process developed in eukaryotes to recycle molecules for adaptation to various environments. Autophagy is speculated to play a role in pathogen virulence by supplying sources of essential proteins for survival in severe host environments. Here, we investigated the effects of defective autophagy on C. glabrata virulence. Autophagy was induced by nitrogen starvation and hydrogen peroxide (H2O2) in C. glabrata. A mutant strain lacking CgAtg1, an autophagy-inducing factor, was generated and confirmed to be deficient for autophagy. The Cgatg1Δ strain was sensitive to nitrogen starvation and H2O2, died rapidly in water without any nutrients, and showed high intracellular ROS levels compared with the wild-type strain and the CgATG1-reconstituted strain in vitro. Upon infecting mouse peritoneal macrophages, the Cgatg1Δ strain showed higher mortality from phagocytosis by macrophages. Finally, in vivo experiments were performed using two mouse models of disseminated candidiasis and intra-abdominal candidiasis. The Cgatg1Δ strain showed significantly decreased CFUs in the organs of the two mouse models. These results suggest that autophagy contributes to C. glabrata virulence by conferring resistance to unstable nutrient environments and immune defense of hosts, and that Atg1 is a novel fitness factor in Candida species.

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[Ectopic pulmonary calcification after parathyroidectomy in multiple myeloma].

Koji Ando, Yoshitaka Imaizumi, Kazuko Yamamoto, Moe Tanaka, Yoshiaki Zaizen, Masataka Taguchi, Chika Sakaki, Masahiro Ichinose, Takafumi Furumoto, Miki Hashimoto, Machiko Fujioka, Hikaru Sakamoto, Makiko Hourai, Hidehiro Itonaga, Shinya Sato, Yasushi Sawayama, Tomoko Hata, Hiroshi Mukae, Junya Fukuoka, Daisuke Inoue, Yasushi Miyazaki

[Rinsho ketsueki] The Japanese journal of clinical hematology   60 ( 7 ) 785 - 790   2019年 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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Ectopic soft tissue calcification (ESTC), a rare clinical condition, causes tissue and organ damage. It is associated with chronic renal failure, hyperparathyroidism, and malignant neoplasms, including multiple myeloma, and it is reportedly resistant to treatment. Here, we present the case of a 71-year-old male with multiple myeloma who had rapid ESTC in the lung. He had developed hypoparathyroidism secondary to thyroidectomy. During the course of our observation, he rapidly developed ectopic pulmonary calcification approximately 2 weeks after acquiring an infection. There was no evidence of further progression of multiple myeloma after the onset of ESTC, and treatment with ferric citrate hydrate and precipitated calcium resulted in immediate improvement of his pulmonary signs. We recommend cautious monitoring for patients with multiple myeloma and hypoparathyroidism to detect the onset of ectopic calcification. In addition, low blood phosphorus levels should be effectively treated.

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Clinical and Microbiological Characteristics of Candida guilliermondii and Candida fermentati.

Tatsuro Hirayama, Taiga Miyazaki, Yuka Yamagishi, Hiroshige Mikamo, Takashi Ueda, Kazuhiko Nakajima, Yoshio Takesue, Yoshitsugu Higashi, Yoshihiro Yamamoto, Muneyoshi Kimura, Hideki Araoka, Shuichi Taniguchi, Yuichi Fukuda, Yumi Matsuo, Akiko Furutani, Kohei Yamashita, Takahiro Takazono, Tomomi Saijo, Shintaro Shimamura, Kazuko Yamamoto, Yoshifumi Imamura, Koichi Izumikawa, Katsunori Yanagihara, Shigeru Kohno, Hiroshi Mukae

Antimicrobial agents and chemotherapy   62 ( 6 )   2018年06月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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A total of 46 clinical isolates of Candida guilliermondii and Candida famata were reidentified genetically, resulting in 27 C. guilliermondii and 12 Candida fermentati strains. The majority of C. guilliermondii strains, but not C. fermentati strains, were isolated from blood cultures. C. fermentati was more sensitive to antifungals, hydrogen peroxide, and killing by murine macrophages than was C. guilliermondii The C. guilliermondii isolates were echinocandin susceptible in vitro but resistant to micafungin in a murine model of invasive candidiasis.

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Examination of cryptococcal glucuronoxylomannan antigen in bronchoalveolar lavage fluid for diagnosing pulmonary cryptococcosis in HIV-negative patients.

Kazuhiro Oshima, Takahiro Takazono, Tomomi Saijo, Masato Tashiro, Shintaro Kurihara, Kazuko Yamamoto, Yoshifumi Imamura, Taiga Miyazaki, Misuzu Tsukamoto, Katsunori Yanagihara, Hiroshi Mukae, Shigeru Kohno, Koichi Izumikawa

Medical mycology   56 ( 1 ) 88 - 94   2018年01月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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We clarified the performance of a cryptococcal glucuronoxylomannan (GXM) antigen test using bronchoalveolar lavage fluid (BALF) samples, in an HIV-negative Japanese population. Between March 2008 and December 2014, we examined cryptococcal GXM antigens in both serum and BALF specimens from 429 cases at Nagasaki University hospital. The diagnoses, underlying diseases, chest computed tomography findings, and cryptococcal GXM antigen test results were retrospectively investigated. Twenty-three patients were confirmed to have pulmonary cryptococcosis, another six were clinically diagnosed with cryptococcosis because they were seropositive for the GXM antigen, and five possible cryptococcosis cases had BALF samples that were positive for the GXM antigen and serum samples that were negative. The test's sensitivities for detecting cryptococcal GXM antigens in serum and BALF samples, for confirmed cases, were 73.9% and 82.6%, respectively, and their respective specificities were 98.5% and 97.8%. Three of the five putative patients with cryptococcosis were treated with antifungal agents; the pulmonary lesions decreased in size in all treated patients. Both the BALF and serum GXM antigen titers showed positive correlations with the lesion sizes; however, the serum antigen titers showed a higher correlation (r = 0.490, P = .0033) than did the BALF titres (r = 0.312, P = .0724). The rate of GXM-positive BALF samples was higher than the rate for serum samples, especially for patients with pulmonary lesion diameters ≤25 mm. Testing for the presence of the cryptococcal GXM antigen in BALF specimens might contribute to the early diagnosis of pulmonary cryptococcosis.

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Regionally compartmentalized resident memory T cells mediate naturally acquired protection against pneumococcal pneumonia.

Smith NMS, WassermanGA, Coleman FT, Hilliard KL, Yamamoto K, Lipsitz E, Malley R, Dooms H, Jones MR, Quinton LJ, Mizgerd JP

Mucosal Immunology   11 ( 1 ) 220 - 235   2018年01月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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Comparison of Efficacy of Antimicrobial Agents among Hospitalized Patients with Mycoplasma pneumoniae Pneumonia in Japan during Large Epidemics of Macrolide-Resistant M. pneumoniae Infections: A Nationwide Observational Study

Masato Tashiro, Kiyohide Fushimi, Kei Kawano, Takahiro Takazono, Tomomi Saijo, Kazuko Yamamoto, Shintaro Kurihara, Yoshifumi Imamura, Taiga Miyazaki, Katsunori Yanagihara, Hiroshi Mukae, Koichi Izumikawa

Clinical Infectious Diseases ( Oxford University Press )  65 ( 11 ) 1837 - 1842   2017年12月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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Background Mycoplasma pneumoniae strains with resistance to macrolides have been spreading worldwide. Here, we aimed to clarify which antimicrobial agent is a better treatment for patients with M. pneumoniae pneumonia in a setting with large epidemics of macrolide resistance. Methods Adult patients hospitalized with laboratory-confirmed M. pneumoniae pneumonia from 2010 to 2013 were identified from the Japanese Diagnosis Procedure Combination national database. Drug switching, length of stay (LOS), 30-day mortality, and total costs for patients who underwent macrolide, quinolone, and tetracycline therapy were compared using propensity score analyses. Results Eligible patients (N = 1650) from 602 hospitals were divided into the macrolide group (n = 508), quinolone group (n = 569), or tetracycline group (n = 573). We found that 52.8%, 21.8%, and 38.6% of patients in the macrolide, quinolone, and tetracycline groups, respectively, had to switch drugs (P &lt .0001). There was no significant difference in the LOS and the 30-day mortality rates among these 3 groups. Cost was highest in the quinolone group (P =.0062). The propensity score-matched pairs (n = 487×2) generated from the quinolone and tetracycline groups also showed a lower proportion of patients who require switches in the quinolone group than in the tetracycline group (21.2% vs 39.6%, P &lt .0001) but not in the LOS, mortality, and cost. Conclusions There were no significant differences in the LOS and mortality among any antimycoplasmal drugs as initial treatment for hospitalized M. pneumoniae pneumonia patients despite the lower switching rate in the quinolone group.

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Adjunctive corticosteroid therapy for inpatients with &ITMycoplasma pneumoniae&IT pneumonia

Masato Tashiro, Kiyohide Fushimi, Kei Kawano, Takahiro Takazono, Tomomi Saijo, Kazuko Yamamoto, Shintaro Kurihara, Yoshifumi Imamura, Taiga Miyazaki, Katsunori Yanagihara, Hiroshi Mukae, Koichi Izumikawa

BMC PULMONARY MEDICINE ( BIOMED CENTRAL LTD )  17 ( 1 ) 219   2017年12月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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Background: There is conflicting evidence regarding the benefit of adjunctive corticosteroid therapy in patients with Mycoplasma pneumoniae pneumonia. We hypothesised that corticosteroid therapy could reduce mortality and length of stay (LOS) in such patients.& para;& para;Methods: Adult patients with M. pneumoniae pneumonia from January 2010 to December 2013 were identified from the Japanese Diagnosis Procedure Combination inpatient database. The effects of low-dose and high-dose corticosteroid therapies on mortality, LOS, drug costs and hyperglycaemia requiring insulin treatment were evaluated using propensity score analyses.& para;& para;Results: Eligible patients (n = 2228) from 630 hospitals were divided into no-corticosteroid (n = 1829), low-dose corticosteroid (n = 267) and high-dose corticosteroid (n = 132) groups. The propensity score-matched pairs were generated from no-corticoid and low-dose corticoid groups (251 pairs), or no-corticoid and high-dose corticosteroid groups (120 pairs). Adjunctive corticosteroid therapy did not decrease 30-day mortality. In addition, both low-dose and high-dose corticosteroid therapies were associated with increases in LOS. Furthermore, hyperglycaemia requiring insulin treatment and drug cost increased with corticosteroid use. & para;& para;Conclusions: Adjunctive treatment with low-dose or high-dose corticosteroids may not be beneficial in M. pneumoniae pneumonia.

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Proposal of a new scoring system to predict prognosis of candidemia patients

Akagi K, Motokawa N, Miyazaki T, Saijo T, Yamamoto K, Imamura Y, Izumikawa K, Yanagihara K, Kohno S, Mukae H

International Journal of Antimicrobial Agents   50   S32   2017年11月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

Expression of Piwi protein MIWI2 defines a distinct population of multiciliated cells

Gregory A. Wasserman, Aleksander D. Szymaniak, Anne C. Hinds, Kazuko Yamamoto, Hirofumi Kamata, Nicole M. S. Smith, Kristie L. Hilliard, Claudia Carrieri, Adam T. Labadorf, Lee J. Quinton, Xingbin Ai, Xaralabos Varelas, Felicia Chen, Joseph P. Mizgerd, Alan Fine, Donal O'Carroll, Matthew R. Jones

JOURNAL OF CLINICAL INVESTIGATION ( AMER SOC CLINICAL INVESTIGATION INC )  127 ( 10 ) 3866 - 3876   2017年10月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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P-element-induced wimpy testes (Piwi) proteins are known for suppressing retrotransposon activation in the mammalian germline. However, whether Piwi protein or Piwi-dependent functions occur in the mammalian soma is unclear. Contrary to germline-restricted expression, we observed that Piwi-like Miwi2 mRNA is indeed expressed in epithelial cells of the lung in adult mice and that it is induced during pneumonia. Further investigation revealed that MIWI2 protein localized to the cytoplasm of a discrete population of multiciliated airway epithelial cells. Isolation and next-generation sequencing of MIWI2-positive multiciliated cells revealed that they are phenotypically distinct from neighboring MIWI2-negative multiciliated cells. Mice lacking MIWI2 exhibited an altered balance of airway epithelial cells, demonstrating fewer multiciliated cells and an increase in club cells. During pneumococcal pneumonia, Miwi2-deficient mice exhibited increased expression of inflammatory mediators and increased immune cell recruitment, leading to enhanced bacterial clearance. Taken together, our data delineate MIWI2-dependent functions outside of the germline and demonstrate the presence of distinct subsets of airway multiciliated cells that can be discriminated by MIWI2 expression. By demonstrating roles for MIWI2 in airway cell identity and pulmonary innate immunity, these studies elucidate unanticipated physiological functions for Piwi proteins in somatic tissues.

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Capacity of Pneumococci to Activate Macrophage Nuclear Factor κB: Influence on Necroptosis and Pneumonia Severity.

Coleman FT, Blahna MT, Kamata H, Yamamoto K, Zabinski MC, Kramnik I, Wilson AA, Kotton DN, Quinton LJ, Jones MR, Pelton SI, Mizgerd JP

The Journal of infectious diseases ( OXFORD UNIV PRESS INC )  216 ( 4 ) 425 - 435   2017年08月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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3 During pneumococcal pneumonia, antibacterial defense requires the orchestrated expression of innate immunity mediators, initiated by alveolar macrophages and dependent on transcription driven by nuclear factor kappa B (NF-kappa B). Such immune pressure may select for pneumococci, which avoid or subvert macrophage NF-kappa B activation. Analyzing pneumococci collected from children in Massachusetts, we found that the activation of macrophage NF-kappa B by Streptococcus pneumoniae is highly diverse, with a preponderance of low NF-kappa B activators that associate particularly with complicated pneumonia. Low NF-kappa B activators cause more severe lung infections in mice, and they drive macrophages toward an alternate and detrimental cell fate of necroptosis. Both outcomes can be reversed by activation of macrophages with pneumococci that are high NF-kappa B activators. These results suggest that low NF-kappa B activation is a virulence property of pneumococci and that the appropriate activation of macrophages, including NF-kappa B, may hold promise as an adjunct therapeutic avenue for pneumococcal pneumonia.

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In vitro and in vivo antifungal activities of T-2307, a novel arylamidine, against Cryptococcus gattii: an emerging fungal pathogen

Hiroshi Nishikawa, Yoshiko Fukuda, Junichi Mitsuyama, Masato Tashiro, Akitaka Tanaka, Takahiro Takazono, Tomomi Saijo, Kazuko Yamamoto, Shigeki Nakamura, Yoshifumi Imamura, Taiga Miyazaki, Hiroshi Kakeya, Yoshihiro Yamamoto, Katsunori Yanagihara, Hiroshi Mukae, Shigeru Kohno, Koichi Izumikawa

JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY ( OXFORD UNIV PRESS )  72 ( 6 ) 1709 - 1713   2017年06月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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Objectives: T-2307, a novel arylamidine, exhibits potent broad-spectrum activities against the majority of fungal pathogens. In this study, the antifungal activity of T-2307 against Cryptococcus gattii was evaluated in comparison with those of amphotericin B, fluconazole and voriconazole in vitro and in vivo. Methods: The MICs for 15 clinical isolates were determined according to CLSI guidelines and time-kill studies were performed using C. gattii YF2784. In a murine model for intranasal pulmonary infection caused by C. gattii YF2784, the test compounds were administered once daily for 7 days from 2 h or 14 days post-infection. The viable counts in the lungs and brain were determined at 21 days post-infection. Results: The MIC range, MIC50, MIC90 and geometric mean MIC of T-2307 were 0.0078-0.0625, 0.0313, 0.0625 and 0.0394 mg/L, respectively. The MIC of T-2307 was significantly lower than those of fluconazole, voriconazole and amphotericin B. T-2307 showed concentration-dependent fungicidal activity at 4 times the MIC or higher. Administration of T-2307 at 2 mg/kg/day, amphotericin B at 1 mg/kg/day and fluconazole at 160 mg/kg/day from 2 h post-infection significantly reduced viable counts in the lungs and brain. However, when the administration was started 14 days post-infection, only T-2307 significantly reduced the viable counts in both the lungs and the brain at 1 mg/kg/day. Conclusions: T-2307 shows excellent in vitro and in vivo antifungal activities against C. gattii and would be a promising new candidate for the treatment of cryptococcosis.

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A multicenter randomized controlled study on the efficacy of moxifloxacin and garenoxacin for the treatment of adult community-acquired pneumonia

Yoshifumi Imamura, Akitaka Tanaka, Masato Tashiro, Tomomi Saijo, Kazuko Yamamoto, Taiga Miyazaki, Misuzu Tsukamoto, Koichi Izumikawa, Katsunori Yanagihara, Hiroshi Mukae, Shigeru Kohno

Japanese Journal of Chemotherapy   65   168 - 174   2017年03月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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The clinical efficacy and safety of moxifloxacin (MFLX) and garenoxacin (GRNX), two respiratory qui-nolones used as key outpatient treatments for community-acquired pneumonia, were compared in a prospective multicenter randomized controlled study. The study involved 120 adults with mild or moderate community-acquired pneumonia who had visited the Second Department of Internal Medicine of Nagasaki University Hospital or any of 12 associated hospitals between May 2011 and April 2013. The subjects were randomly assigned to receive either MFLX (400 mg/day) or GRNX (400 mg/day); after up to 10 days of oral administration, the efficacy and safety results were compared between the two groups. The numbers of subjects in each analysis set were as follows: efficacy analysis, 111 (MFLX, 54; GRNX, 57); clinical efficacy at the end of treatment, 111 (MFLX, 54; GRNX, 57); bacteriological efficacy analysis, 52 (MFLX, 23; GRNX, 29); and safety analysis, 120 (MFLX, 59; GRNX, 61). The efficacy rate on the 5th to 10th day of post-treatment, defined as the primary endpoint, was 88.9% for the MFLX group and 89.5% for the GRNX group, with no statistically significant difference between the groups. Secondary endpoints, consisting of the efficacy rate on the 3rd day after the initiation of treatment (77.8% for MFLX vs. 73.7% for GRNX), the efficacy rate at the end of treatment (96.3% for MFLX vs. 93.0% for GRNX), and the bacteriological eradication rate (82.6% for MFLX vs. 96.6% for GRNX) were also comparable for both groups, with no statistically significant difference. The incidences of adverse events in the MFLX and GRNX groups were 27.1% and 31.1%, respectively, and no serious adverse events were observed. These results indicate that for the outpatient treatment of adults with mild or moderate community-acquired pneumonia, MFLX and GRNX are comparable with regard to their clinical efficacy and safety.

Epithelial Cell-Derived Secreted and Transmembrane 1a Signals to Activated Neutrophils during Pneumococcal Pneumonia

Hirofumi Kamata, Kazuko Yamamoto, Gregory A. Wasserman, Mary C. Zabinski, Constance K. Yuen, Wing Yi Lung, Adam C. Gower, Anna C. Belkina, Maria I. Ramirez, Jane C. Deng, Lee J. Quinton, Matthew R. Jones, Joseph P. Mizgerd

AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY ( AMER THORACIC SOC )  55 ( 3 ) 407 - 418   2016年09月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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Airway epithelial cell responses are critical to the outcome of lung infection. In this study, we aimed to identify unique contributions of epithelial cells during lung infection. To differentiate genes induced selectively in epithelial cells during pneumonia, we compared genome-wide expression profiles from three sorted cell populations: epithelial cells from uninfected mouse lungs, epithelial cells from mouse lungs with pneumococcal pneumonia, and nonepithelial cells from those same infected lungs. Of 1,166 transcripts that were more abundant in epithelial cells from infected lungs compared with nonepithelial cells from the same lungs or from epithelial cells of uninfected lungs, 32 genes were identified as highly expressed secreted products. Especially strong signals included two related secreted and transmembrane (Sectm) 1 genes, Sectm1a and Sectm1b. Refinement of sorting strategies suggested that both Sectm1 products were induced predominantly in conducting airway epithelial cells. Sectm1 was induced during the early stages of pneumococcal pneumonia, and mutation of NF-kappa B RelA in epithelial cells did not diminish its expression. Instead, type I IFN signaling was necessary and sufficient for Sectm1 induction in lung epithelial cells, mediated by signal transducer and activator of transcription 1. For target cells, Sectm1a bound to myeloid cells preferentially, in particular Ly6G(bright)CD11b(bright) neutrophils in the infected lung. In contrast, Sectm1a did not bind to neutrophils from uninfected lungs. Sectm1a increased expression of the neutrophil-attracting chemokine CXCL2 by neutrophils from the infected lung. We propose that Sectm1a is an epithelial product that sustains a positive feedback loop amplifying neutrophilic inflammation during pneumococcal pneumonia.

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Relapsed Pulmonary Cryptococcosis during Tumor Necrosis Factor α Inhibitor Treatment.

Takazono T, Sawai T, Tashiro M, Saijo T, Yamamoto K, Imamura Y, Miyazaki T, Suyama N, Izumikawa K, Kakeya H, Yanagihara K, Mukae H, Kohno S

Internal medicine (Tokyo, Japan) ( JAPAN SOC INTERNAL MEDICINE )  55 ( 19 ) 2877 - 2880   2016年 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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A 35-year-old non-HIV patient developed pulmonary cryptococcosis after the initiation of infliximab. He recovered by fluconazole treatment and completed the therapy for a total of 6 months. However, he experienced a relapse 16 months later during retreatment with infliximab, revealing an interesting clinical course contradicting retreatment. This case also represents the first case of relapsed pulmonary cryptococcosis suspected during treatment with a biologic agent. Both of these aspects generated important clinical questions about the length of pulmonary cryptococcosis treatment and the necessity of introducing a second prophylaxis for such patients.

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Recurrent Streptococcus agalactiae Toxic Shock Syndrome Triggered by a Tumor Necrosis Factor-α Inhibitor.

Yoshida M, Takazono T, Tashiro M, Saijo T, Morinaga Y, Yamamoto K, Nakamura S, Imamura Y, Miyazaki T, Sawai T, Nishino T, Izumikawa K, Yanagihara K, Mukae H, Kohno S

Internal medicine (Tokyo, Japan) ( JAPAN SOC INTERNAL MEDICINE )  55 ( 21 ) 3211 - 3214   2016年 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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Streptococcal toxic shock syndrome caused by group B streptococcus (GBS) is a rare, but lethal disease. We experienced a 45-year-old woman with pustular psoriasis who developed toxic shock-like syndrome during infliximab treatment. Surprisingly, similar episodes recurred three times in one year with restarting of infliximab treatments. In the third episode, GBS were detected in blood, urine, and vaginal secretion cultures. These episodes of shock syndrome were possibly due to GBS. To the best of our knowledge, this is the first case report of recurrent streptococcal toxic shock syndrome possibly caused by GBS which was induced by anti-TNF-alpha inhibitor therapy. The restarting of biological agents in patients with a history of toxic shock syndrome should therefore be avoided as much as possible.

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An Autopsy Case of Lepidic Pulmonary Metastasis from Cholangiocarcinoma

Yohsuke Nagayoshi, Kazuko Yamamoto, Satoru Hashimoto, Keiko Hisatomi, Seiji Doi, Seiji Nagashima, Hirokazu Kurohama, Masahiro Ito, Takahiro Takazono, Shigeki Nakamura, Taiga Miyazaki, Shigeru Kohno

INTERNAL MEDICINE ( JAPAN SOC INTERNAL MEDICINE )  55 ( 19 ) 2849 - 2853   2016年 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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We herein report the first case of pulmonary metastasis with lepidic growth that originated from cholangiocarcinoma. A 77-year-old man was admitted to our hospital due to exertional dyspnea and liver dysfunction. Computed tomography showed widespread infiltration and a ground-glass opacity in the lung and dilation of the intrahepatic bile duct. The pulmonary lesion progressed rapidly, and the patient died of respiratory failure. Cholangiocarcinoma and lepidic pulmonary metastasis were pathologically diagnosed by an autopsy. Lepidic pulmonary growth is an atypical pattern of metastasis, and immunopathological staining is useful to distinguish pulmonary metastasis from extrapulmonary cancer and primary pulmonary adenocarcinoma.

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Induction of STAT3-Dependent CXCL5 Expression and Neutrophil Recruitment by Oncostatin-M during Pneumonia

Katrina E. Traber, Kristie L. Hilliard, Eri Allen, Gregory A. Wasserman, Kazuko Yamamoto, Matthew R. Jones, Joseph P. Mizgerd, Lee J. Quinton

AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY ( AMER THORACIC SOC )  53 ( 4 ) 479 - 488   2015年10月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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Acute bacterial pneumonia is a significant public health concern worldwide. Understanding the signals coordinating lung innate immunity may foster the development of therapeutics that limit tissue damage and promote host defense. We have previously shown that lung messenger RNA expression of the IL-6 family cytokine oncostatin-M (OSM) is significantly elevated in response to bacterial stimuli. However, its physiological significance during pneumonia is unknown. Here we demonstrate that OSM is rapidly increased in the airspaces of mice after pulmonary infection with Escherichia coli. Neutralization of OSM caused a substantial decrease in airspace neutrophils and macrophages. OSM blockade also caused a marked reduction in lung chemokine (C-X-C motif) ligand (CXCL) 5 expression, whereas other closely related neutrophil chemokines, CXCL1 and CXCL2, were unaffected. Intratracheal administration of recombinant OSM was sufficient to recapitulate the effect on CXCL5 induction, associated with robust activation of the signal transducer and activator of transcription 3 (STAT3) transcription factor. Cell sorting revealed that OSM effects were specific to lung epithelial cells, including a positive feedback loop in which OSM may facilitate expression of its own receptor. Finally, in vitro studies demonstrated that STAT3 was required for maximal OSM-induced CXCL5 expression. These studies demonstrate a novel role for OSM during pneumonia as an important signal to epithelial cells for chemokine induction mediating neutrophil recruitment.

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The Lung-Liver Axis: A Requirement for Maximal Innate Immunity and Hepatoprotection during Pneumonia

Hilliard KL, Allen E, Traber KE, Yamamoto K, Stauffer NM, Wasserman GA, Jones MR, Mizgerd JP, Quinton LJ

AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY ( AMER THORACIC SOC )  53 ( 3 ) 378 - 390   2015年09月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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The hepatic acute-phase response (APR), stimulated by injury or inflammation, is characterized by significant changes in circulating acute-phase protein (APP) concentrations. Although individual functions of liver-derived APPs are known, the net consequence of APP changes is unclear. Pneumonia, which induces the APR, causes an inflammatory response within the airspaces that is coordinated largely by alveolar macrophages and is typified by cytokine production, leukocyte recruitment, and plasma extravasation, the latter of which may enable delivery of hepatocyte-derived APPs to the infection site. To determine the functional significance of the hepatic APR during pneumonia, we challenged APR-null mice lacking hepatocyte signal transducer and activator of transcription 3 (STAT3) and v-rel avian reticuloendotheliosis viral oncogene homolog A (RelA) with Escherichia coli in the airspaces. APR-null mice displayed ablated APP induction, significantly increased mortality, liver injury and apoptosis, and a trend toward increased bacterial burdens. TNF-alpha neutralization reversed hepatotoxicity, but not mortality, suggesting that APR-dependent survival is not solely due to hepatoprotection. After a milder (nonlethal) E. coli infection, hepatocyte-specific mutations decreased APP concentrations and pulmonary inflammation in bronchoalveolar lavage fluid. Cytokine expression in airspace macrophages, but not other airspace or circulating cells, was significantly dependent on APP extravasation into the alveoli. These data identify a novel signaling axis whereby the liver response enhances macrophage activation and pulmonary inflammation during pneumonia. Although hepatic acute-phase changes directly curb injury induced by TNF-alpha in the liver itself, APPs downstream of these same signals promote survival in association with innate immunity in the lungs, thus demonstrating a critical role for the lung-liver axis during pneumonia.

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The lung-liver axis facilitates pulmonary innate immunity and hepatoprotection during pneumonia.

Hilliard KL, Allen E, Traber KE, Yamamoto K, Stauffer NM, Wasserman GA, Jones MR, Mizgerd JP, Quinton LJ

American journal of respiratory cell and molecular biology   53 ( 3 ) 479 - 488   2015年09月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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